WO2024121632A1 - Use of anti-cd117 antibody drug conjugate (adc) - Google Patents
Use of anti-cd117 antibody drug conjugate (adc) Download PDFInfo
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- WO2024121632A1 WO2024121632A1 PCT/IB2023/059716 IB2023059716W WO2024121632A1 WO 2024121632 A1 WO2024121632 A1 WO 2024121632A1 IB 2023059716 W IB2023059716 W IB 2023059716W WO 2024121632 A1 WO2024121632 A1 WO 2024121632A1
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Classifications
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- A—HUMAN NECESSITIES
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
- A61K47/6817—Toxins
- A61K47/6831—Fungal toxins, e.g. alpha sarcine, mitogillin, zinniol or restrictocin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/77—Internalization into the cell
Definitions
- CD117 also referred to as c-kit or Stem Cell Factor Receptor (SCRF)
- SCRF Stem Cell Factor Receptor
- SCF Stem Cell Factor Receptor
- CD117 is highly expressed on hematopoietic stem cells (HSCs).
- HSCs hematopoietic stem cells
- Current conditioning regimens which are non- selective and used with toxic multi-dosing regimens limit the use of HSCT due to regimen- related mortality and morbidities including organ toxicity, infertility, and secondary malignancies.
- anti-CD117 based therapy that is effective for conditioning responses, including within stem cell and reticulocytes populations. Summary Described herein are methods for targeted conditioning a human patient for a hematopoietic stem cell transplantation, as well as gene therapy.
- the present invention provides a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of from about 0.02 to about 3.0 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, and wherein the antibody comprises a heavy chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 3, 4, and 5, respectively, and comprises a light chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 6, 7, and 8, respectively, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- the present invention provides a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of from about 0.02 to about 3.0 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, and wherein the anti-CD117 antibody comprises a heavy chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 3, 4, and 5, respectively, and comprises a light chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 6, 7, and 8, respectively, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- the present invention provides an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, and wherein the antibody comprises a heavy chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 3, 4, and 5, respectively, and comprises a light chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 6, 7, and 8, respectively, for use in depleting a population of CD117+ cells in a human patient in need thereof, wherein the ADC is administered to the patient in a dosage of from about 0.02 to about 3.0 mg/kg.
- ADC anti-CD117 antibody drug conjugate
- the present invention provides an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, and wherein the antibody comprises a heavy chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 3, 4, and 5, respectively, and comprises a light chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 6, 7, and 8, respectively, for use in conditioning a human patient for an hematopoietic stem cell (HSC) transplant, wherein the ADC is administered to the patient in a dosage of from about 0.02 to about 3.0 mg/kg.
- ADC anti-CD117 antibody drug conjugate
- the dosage is be selected from the group consisting of about 0.02, 0.04, 0.076, 0.08.0.127, 0.13, 0.15, 0.19, 0.247, 0.30, 0.309, 0.386, 0.483, 0.603, 0.754, 0.942, 1.0, and 3.0 mg/kg.
- the dosage is about 0.02 mg/kg.
- the dosage is about 0.04 mg/kg.
- the dosage is about 0.076 mg/kg.
- the dosage is about 0.08 mg/kg.
- the dosage is about 0.127 mg/kg.
- the dosage is about 0.13 mg/kg.
- the dosage is about 0.15 mg/kg.
- the dosage is about 0.19 mg/kg. In some embodiments, the dosage is about 0.247 mg/kg. In some embodiments, the dosage is about 0.30 mg/kg. In some embodiments, the dosage is about 0.309 mg/kg. In some embodiments, the dosage is about 0.386 mg/kg. In some embodiments, the dosage is about 0.483 mg/kg. In some embodiments, the dosage is about 0.603 mg/kg. In some embodiments, the dosage is about 0.754 mg/kg. In some embodiments, the dosage is about 0.942 mg/kg. In some embodiments, the dosage is about 1.0 mg/kg. In some embodiments, the dosage is about 2.0 mg/kg. In some embodiments, the dosage is about 3.0 mg/kg.
- the dosage is 0.02 mg/kg. In some embodiments, the dosage is 0.04 mg/kg. In some embodiments, the dosage is 0.076 mg/kg. In some embodiments, the dosage is 0.08 mg/kg. In some embodiments, the dosage is 0.127 mg/kg. In some embodiments, the dosage is 0.13 mg/kg. In some embodiments, the dosage is 0.15 mg/kg. In some embodiments, the dosage is 0.19 mg/kg. In some embodiments, the dosage is 0.247 mg/kg. In some embodiments, the dosage is 0.30 mg/kg. In some embodiments, the dosage is 0.309 mg/kg. In some embodiments, the dosage is 0.386 mg/kg. In some embodiments, the dosage is 0.483 mg/kg.
- the dosage is 0.603 mg/kg. In some embodiments, the dosage is 0.754 mg/kg. In some embodiments, the dosage is 0.942 mg/kg. In some embodiments, the dosage is 1.0 mg/kg. In some embodiments, the dosage is 2.0 mg/kg. In some embodiments, the dosage is 3.0 mg/kg.
- the anti-CD117 antibody comprises a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 2. In some preferred embodiments, the antibody comprises a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 9 and a light chain having an amino acid sequence as set forth in SEQ ID NO: 10.
- the anti-CD117 antibody comprises an Fc region comprising a D265C mutation (according to EU index). In some preferred embodiments, the anti-CD117 antibody comprises an Fc region comprising a L234A mutation and a L235A mutation (according to EU index). In some preferred embodiments, the anti-CD117 antibody comprises an Fc region comprising a H435A mutation (according to EU index).
- the ADC has the structure of formula (I): (Formula I), or a stereoisomer thereof; wherein: Q is S; Ab is the anti-CD117 antibody; and L-Z is , wherein represents the point of attachment to the antibody (Ab) and represents the point of attachment to the amatoxin. In some preferred embodiments, the anti-CD117 ADC has a structure according to Formula Ia:
- the ADC has the structure of formula (III): (III), or a stereoisomer thereof; wherein: X is S or S(O); L is a linker; Z is a chemical moiety formed by a coupling reaction between a reactive substituent Z' present on L and a reactive substituent present within the anti-CD117 antibody; and Ab is the anti-CD117 antibody.
- the ADC has the structure of formula (IV): (IV), wherein Ab is the anti-CD117 antibody.
- the methods and uses described above further comprise a administering a cell transplantation to the human patient.
- the cell transplantation comprises a population of stem cells.
- the stem cells are allogeneic.
- the human patient has a cancer.
- the cancer is a leukemia.
- the leukemia is relapsed or refractory acute myeloid leukemia.
- the human patient has myelodysplasia, e.g., myelodysplasia with excess blasts (MDS-EB).
- the cell transplantation comprises genetically modified cells.
- the human patient has a hemoglobinapthy or a lysosomal disorder.
- the human patient is administered a single dose of the anti-CD117 ADC.
- the anti-CD117 ADC is administered to the human patient intravenously. In some preferred embodiments, the patient is administered a second dose of the anti-CD117 ADC upon achieving a partial remission.
- the human subject has at least one of the following characteristics: is an adult who is age 18-75 inclusive; has an identified HSCT donor prior to administration of the anti-CD117 ADC; and has an Eastern Cooperative Oncology Group (ECOG) performance status of ⁇ 2; has no significant organ dysfunction prior to administration of the anti-CD117 ADC; has no systemic infections prior to administration of the anti-CD117 ADC; has no APL, active CNS leukemia or chloroma prior to administration of the anti-CD117 ADC; or has had washouts for prior anti-leukemic therapies prior to administration of the anti- CD117 ADC.
- ECG Eastern Cooperative Oncology Group
- the human subject does not have at least one of the following characteristics prior to administration of the anti-CD117 ADC: acute promyelocytic leukemia (APL); active central nervous system (CNS) leukemia; chloroma (granulocyte sarcoma); received an HSC transplant within 6 months of being selected for treatment; active graft-versus-host disease (GVHD); active hepatitis B (Hep-B) or hepatitis C (Hep-C) infection; a history of human immunodeficiency virus (HIV); a QTc value >470 msec; has received another investigational drug or device within 30 days; active uncontrolled systemic bacterial, fungal, or viral infection; any systemic antileukemia treatment within 14 days except hydroxyurea; received prior ADC treatment or anti-CD117 antibody treatment; received recent monoclonal antibody therapy within the last 30 days; received recent vaccination within the last 14 days; or Grade 2 or higher electrolyte abnormality at screening.
- APL acute promyelocytic leuk
- the present invention provides a method of depleting CD117+ cells in a human subject having a hematological cancer, the method comprising administering an anti-CD117 antibody drug conjugate (ADC) to the human subject having a hematological cancer, thereby depleting CD117+ cells in the subject, wherein the anti-CD117 ADC comprises an anti-CD117 antibody (Ab) conjugated via a linker (L) to an amatoxin (Am), wherein the anti- CD117 ADC has a structure selected from the group consisting of Formula I: HO (Formula I), or a stereoisomer thereof; wherein: Q is S; Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light
- X is S or S(O); L is a linker; Z is a chemical moiety formed by a coupling reaction between a reactive substituent Z' present on L and a reactive substituent present within the anti-CD117 antibody; and Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:7, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 8; and formula (IV):
- Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:7, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 8.
- present invention provides an antibody drug conjugate (ADC) comprising an anti-CD117 antibody (Ab) conjugated via a linker (L) to an amatoxin (Am) for use in depleting CD117+ cells in a human subject having a hematological cancer, wherein the anti- CD117 ADC has a structure selected from the group consisting of Formula I:
- Form I (Formula I), or a stereoisomer thereof; wherein: Q is S; Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:7, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 8; L-Z is , wherei n represents the point of attachment to the antibody (Ab) and represents the point of attachment to the amatoxin; formula (III):
- X is S or S(O); L is a linker; Z is a chemical moiety formed by a coupling reaction between a reactive substituent Z' present on L and a reactive substituent present within the anti-CD117 antibody; and Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:7, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 8; and formula (IV):
- Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:7, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 8.
- the hematologic cancer is Acute Myeloid Leukemia (AML) or Myelodysplasia-Excess Blasts (MDS-EB).
- AML Acute Myeloid Leukemia
- MDS-EB Myelodysplasia-Excess Blasts
- the AML is CD117+ AML.
- the human subject has relapsed or refractory AML (R/R AML).
- the human subject has at least one of the following characteristics: is an adult who is age 18-75 inclusive; has an identified HSCT donor prior to administration of the anti-CD117 ADC; and has an Eastern Cooperative Oncology Group (ECOG) performance status of ⁇ 2; has no significant organ dysfunction prior to administration of the anti-CD117 ADC; has no systemic infections prior to administration of the anti-CD117 ADC; has no APL, active CNS leukemia or chloroma prior to administration of the anti-CD117 ADC; or has had washouts for prior anti-leukemic therapies prior to administration of the anti- CD117 ADC.
- ECG Eastern Cooperative Oncology Group
- the human subject does not have at least one of the following characteristics prior to administration of the anti-CD117 ADC: acute promyelocytic leukemia (APL); active central nervous system (CNS) leukemia; chloroma (granulocyte sarcoma); received an HSC transplant within 6 months of being selected for treatment; active graft-versus-host disease (GVHD); active hepatitis B (Hep-B) or hepatitis C (Hep-C) infection; a history of human immunodeficiency virus (HIV); a QTc value >470 msec; has received another investigational drug or device within 30 days; active uncontrolled systemic bacterial, fungal, or viral infection; any systemic antileukemia treatment within 14 days except hydroxyurea; received prior ADC treatment or anti-CD117 antibody treatment; received recent monoclonal antibody therapy within the last 30 days; received recent vaccination within the last 14 days; or Grade 2 or higher electrolyte abnormality at screening.
- APL acute promyelocytic leuk
- the anti-CD117 ADC is administered to the human subject as a single dose.
- the anti-CD117 antibody comprises a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 1, and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 2.
- the anti-CD117 antibody comprises an Fc region comprising amino acid substitutions L234A, L235A, D265C and H435A.
- the anti-CD117 antibody comprises a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 9 and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 10.
- the anti-CD117 ADC has a structure according to Formula Ia:
- the anti-CD117 ADC is administered to the human subject at a dose of about 0.02 mg/kg. In some preferred embodiments, the anti-CD117 ADC is administered to the human subject at a dose of about 0.04 mg/kg. In some preferred embodiments, the anti-CD117 ADC is administered to the human subject at a dose of about 0.08 mg/kg. In some preferred embodiments, the anti-CD117 ADC is administered to the human subject at a dose of about 0.076 mg/kg. In some preferred embodiments, the anti-CD117 ADC is administered to the human subject at a dose of about 0.13 mg/kg.
- the anti-CD117 ADC is administered to the human subject at a dose of about 0.19 mg/kg. In some preferred embodiments, the human subject is administered a single dose of the anti-CD117 ADC. In some preferred embodiments, the anti-CD117 ADC is administered to the human subject intravenously. In some preferred embodiments, the human subject achieves complete remission of MDS or the hematological cancer.
- Fig.1 graphically depicts the results of a non-human primate (NHP) pharmacokinetic assay expressed as the mean (+/-SD) plasma concentration (ng/mL) of an anti-CD117 antibody drug conjugate (i.e., an anti-CD117 antibody conjugated to an amatoxin) as a function of time (i.e., days post-administration; x-axis) in a NHP after a single intravenous administration of the anti-CD117 antibody drug conjugate at 0.05 mg/kg (triangle), 0.15 mg/kg (square), 0.3 mg/kg (triangle), 0.5 mg/kg (inverted triangle), 1 mg/kg (diamond), and 3 mg/kg (circle) mg/kg.
- NHP non-human primate
- Fig.2 graphically depicts the results of a cell depletion assay expressed as the mean (+/-SD) blood reticulocyte counts (10 9 /L) as a function of time (i.e., days post-administration; x- axis) in a NHP after a single intravenous administration of the anti-CD117 antibody drug conjugate at 0.05 mg/kg (triangle), 0.15 mg/kg (square), 0.3 mg/kg (triangle), 0.5 mg/kg (inverted triangle), 1 mg/kg (diamond), and 3 mg/kg (circle) mg/kg.
- Fig.3A-B depicts the results of a cell depletion assay in bone marrow.
- Fig.3A depicts depletion of stem cells in bone marrow expressed as mean (+/-SD) CD34+/CD90+/CD45RA- counts (10 3 /mL) as a function of time (i.e., days post-administration; x-axis) in a NHP after a single intravenous administration of the anti-CD117 antibody drug conjugate at 0.05 mg/kg (triangle), 0.15 mg/kg (square), 0.3 mg/kg (triangle), 0.5 mg/kg (inverted triangle), 1 mg/kg (diamond), and 3 mg/kg (circle) mg/kg.
- Fig.3B shows the depletion of CD34+/CD90+/CD45RA- stem cells on day 7 post-administration at 0.05 mg/kg, 0.15 mg/kg, 0.3 mg/kg, 0.5 mg/kg, 1 mg/kg, and 3 mg/kg.
- Fig.4 graphically depicts MGTA-117 concentration (ng/mL) as a function of time (hours). Participants in cohort 1 (0.02 mg/kg) are represented by circles, participants in cohort 2 (0.04 mg/kg) are represented by squares, and participants in cohort 3 (0.08 mg/kg) are represented by triangles.
- Fig.5 graphically depicts data showing MGTA-117 rapidly bound to CD117+ blast cells in blood. The percentage of blast cell receptor occupancy as a function of time (hours).
- Fig.6 graphically depicts data showing MGTA-117 depleted CD117+ blast cells in blood for 3 of the cohorts (cohorts 1, 2, and 3). The percentage change in CD117+ blast cells is shown relative to baseline (0). The maximum percent change for an individual participant at any time point is shown.
- Fig.7 shows case study results showing that MGTA-117 depleted CD117+ red blood cell progenitors in bone marrow. The figure shows flow cytometry data from blood marrow samples for participant 3 at screening and following MGTA-117 treatment.
- Fig.8 graphically depicts the absolute percent change from baseline for blast cells in bone marrow. Day 14 results are shown for cohort 1, and day 7 results are shown for cohorts 2 and 3. The results show that MGTA-117 depleted blast cells in the bone marrow.
- Fig.9 presents details of the treatment plan for a participant from cohort 1. The case study was a 58 year old male with FLT3 mutation and treatment refractory AML. The patient had complete remission (CR) observed to date after a single dose of MGTA-117.
- Fig.10 presents details of the treatment plan for a participant from cohort 3.
- the case study was a 73 year old female with ASXL1, BCOR, U2AF1 mutations and treatment refractory MDS.
- the patient had complete remission (CR) observed to date after a single dose of MGTA- 117.
- the invention provides targeted conditioning methods comprising administering an effective dose of an anti-CD117 antibody drug conjugate (ADC) comprising anti-CD117 antibody conjugated to an amatoxin, to a patient in need thereof.
- ADC anti-CD117 antibody drug conjugate
- a refers to a member of the amatoxin family of peptides which are generally produced by Amanita phalloides mushrooms, or a derivative thereof, such as a variant or derivative thereof capable of inhibiting RNA polymerase II activity.
- Amatoxins may be isolated from a variety of mushroom species (e.g., Amanita phalloides, Galerina marginata, Lepiota brunneo-incarnata) or may be prepared semi-synthetically or synthetically. A member of this family, ⁇ amanitin, is described in Wieland, Int. J. Pept. Protein Res.1983, 22(3):257-276.
- a derivative of an amatoxin may be obtained by chemical modification of a naturally occurring compound ("semi-synthetic"), or may be obtained from an entirely synthetic source. Synthetic routes to various amatoxin derivatives are disclosed in, for example, U.S.
- Amatoxins useful in conjunction with the compositions and methods described herein include compounds such, as, but not limited to, compounds of Formula (I), ⁇ -amanitin, ⁇ -amanitin, ⁇ -amanitin, ⁇ -amanitin, amanin, amaninamide, amanullin, amanullinic acid, and proamanullin.
- amatoxins may be conjugated to an antibody, or antigen-binding fragment thereof, for instance, by way of a linker moiety (L) (thus forming an ADC).
- L linker moiety
- the term "antibody” refers to an immunoglobulin molecule that specifically binds to, or is immunologically reactive with, a particular antigen.
- antibodies comprise heavy and light chains containing antigen binding regions. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region.
- the heavy chain constant region is comprised of three domains, CH1, CH2 and CH3.
- Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region.
- the light chain constant region is comprised of one domain, CL.
- the VH, and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
- CDR complementarity determining region
- FR framework regions
- Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
- the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
- the constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
- the amino acid positions that delineate a hypervariable region of an antibody can vary, depending on the context and the various definitions known in the art.
- variable domains may be viewed as hybrid hypervariable positions in that these positions can be deemed to be within a hypervariable region under one set of criteria while being deemed to be outside a hypervariable region under a different set of criteria. One or more of these positions can also be found in extended hypervariable regions.
- the antibodies described herein may contain modifications in these hybrid hypervariable positions.
- the variable domains of native heavy and light chains each contain four framework regions that primarily adopt a ⁇ -sheet configuration, connected by three CDRs, which form loops that connect, and in some cases form part of, the ⁇ -sheet structure.
- the CDRs in each chain are held together in close proximity by the framework regions in the order FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 and, with the CDRs from the other antibody chains, contribute to the formation of the target binding site of antibodies (see Kabat et al., Sequences of Proteins of Immunological Interest, National Institute of Health, Bethesda, MD., 1987).
- numbering of immunoglobulin amino acid residues is performed according to the immunoglobulin amino acid residue numbering system of Kabat et al., unless otherwise indicated (although any antibody numbering scheme, including, but not limited to IMGT and Chothia, can be utilized).
- an “intact” or “full length” antibody refers to an antibody having two heavy (H) chain polypeptides and two light (L) chain polypeptides interconnected by disulfide bonds.
- Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region.
- the heavy chain constant region is comprised of three domains, CH1, CH2 and CH3.
- Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region.
- the light chain constant region is comprised of one domain, CL.
- VH, and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
- CDR complementarity determining regions
- FR framework regions
- Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl- terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
- the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
- the constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
- antibody drug conjugate refers to a compound formed by the chemical bonding of a reactive functional group of one molecule, such as an antibody, with an appropriately reactive functional group of another molecule, such as a cytotoxin described herein.
- the foregoing conjugates are also referred to interchangeably herein as a “drug antibody conjugate” and an “ADC”.
- Conjugates may include a linker between the two molecules bound to one another, e.g., between an antibody and a cytotoxin. Examples of linkers that can be used for the formation of a conjugate include peptide-containing linkers, such as those that contain naturally occurring or non-naturally occurring amino acids, such as D-amino acids.
- Linkers can be prepared using a variety of strategies described herein and known in the art. Depending on the reactive components therein, a linker may be cleaved, for example, by enzymatic hydrolysis, photolysis, hydrolysis under acidic conditions, hydrolysis under basic conditions, oxidation, disulfide reduction, nucleophilic cleavage, or organometallic cleavage (see, for example, Leriche et al., Bioorg. Med. Chem., 20:571-582, 2012).
- anti-CD117 antibody or “an antibody that binds to CD117” refers to an antibody that is capable of binding CD117, e.g., human CD117 (hCD117) with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting CD117.
- condition refers to processes by which a patient is prepared for receipt of a transplant, e.g., a transplant containing hematopoietic stem cells (HSCs).
- a patient may be conditioned for hematopoietic stem cell transplant therapy by administration to the patient of an anti-CD117 ADC.
- Administration of an anti-CD117 ADC to a patient in need of hematopoietic stem cell transplant therapy can promote the engraftment of a hematopoietic stem cell graft, for example, by selectively depleting endogenous hematopoietic stem cells, thereby creating a vacancy filled by an exogenous hematopoietic stem cell transplant.
- HSCs hematopoietic stem cells
- granulocytes e.g., promyelocytes, neutrophils, eosinophils, basophils
- erythrocytes e.g., reticulocytes, erythrocytes
- thrombocytes e.g., megakaryoblasts, platelet producing megakaryocytes, platelets
- monocytes e.g., monocytes, macrophages
- dendritic cells e.g., NK cells, B-cells and T-cells.
- Such cells may include CD34+ cells.
- CD34+ cells are immature cells that express the CD34 cell surface marker. In humans, CD34+ cells are believed to include a subpopulation of cells with the stem cell properties defined above, whereas in mice, HSCs are CD34-.
- HSCs also refer to long term repopulating HSCs (LT-HSC) and short term repopulating HSCs (ST-HSC). LT-HSCs and ST-HSCs are differentiated, based on functional potential and on cell surface marker expression.
- human HSCs are CD34+, CD38-, CD45RA-, CD90+, CD49F+, and lin- (negative for mature lineage markers including CD2, CD3, CD4, CD7, CD8, CD10, CD11B, CD19, CD20, CD56, CD235A).
- bone marrow LT-HSCs are CD34-, SCA-1+, C-kit+, CD135-, Slamfl/CD150+, CD48-, and lin- (negative for mature lineage markers including Ter119, CD11b, Gr1, CD3, CD4, CD8, B220, IL7ra), whereas ST-HSCs are CD34+, SCA-1+, C-kit+, CD135-, Slamfl/CD150+, and lin- (negative for mature lineage markers including Ter119, CD11b, Gr1, CD3, CD4, CD8, B220, IL7ra).
- ST-HSCs are less quiescent and more proliferative than LT-HSCs under homeostatic conditions.
- LT- HSC have greater self-renewal potential (i.e., they survive throughout adulthood, and can be serially transplanted through successive recipients), whereas ST-HSCs have limited self- renewal (i.e., they survive for only a limited period of time, and do not possess serial transplantation potential). Any of these HSCs can be used in the methods described herein. ST-HSCs are particularly useful because they are highly proliferative and thus, can more quickly give rise to differentiated progeny.
- patients that are “in need of” a hematopoietic stem cell transplant include patients that exhibit a defect or deficiency in one or more blood cell types, as well as patients having a stem cell disorder, autoimmune disease, cancer, or other pathology described herein.
- the term “recipient” refers to a patient that receives a transplant, such as a transplant containing a population of cells, e.g., hematopoietic stem cells.
- the transplanted cells administered to a recipient may be, e.g., autologous, syngeneic, or allogeneic cells.
- the terms “subject”, “patient”, and “participant” refer to an organism, such as a human, that receives treatment for a particular disease or condition as described herein.
- a patient such as a human patient, may receive treatment prior to a HSC transplant for depletion of endogenous CD117+ cells.
- the phrase “substantially cleared from the blood” refers to a point in time following administration of a therapeutic agent (such as an anti-CD117 ADC) to a patient when the concentration of the therapeutic agent in a blood sample isolated from the patient is such that the therapeutic agent is not detectable by conventional means (for instance, such that the therapeutic agent is not detectable above the noise threshold of the device or assay used to detect the therapeutic agent).
- a therapeutic agent such as an anti-CD117 ADC
- a variety of techniques known in the art can be used to detect ADCs, antibodies, and antibody fragments, such as ELISA-based detection assays known in the art or described herein. Additional assays that can be used to detect antibodies, or antibody fragments, include immunoprecipitation techniques and immunoblot assays, among others known in the art.
- stem cell disorder broadly refers to any disease, disorder, or condition that may be treated by conditioning a subject's target tissues, and/or by ablating an endogenous stem cell population in a target tissue (e.g., ablating an endogenous hematopoietic stem or progenitor cell population from a subject's bone marrow tissue) and/or by transplanting stem cells in a subject's target tissues.
- diseases that may be treated using the patient conditioning and/or hematopoietic stem cell transplant methods described herein include, but are not limited to, inherited blood disorders (e.g., sickle cell anemia), or a cancer such as a hematologic cancer, such as leukemia, lymphoma, and myeloma.
- a cancer such as a hematologic cancer, such as leukemia, lymphoma, and myeloma.
- the cancer may be acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, multiple myeloma, diffuse large B-cell lymphoma, or non-Hodgkin’s lymphoma.
- the terms “treat” or “treatment” refers to reducing the severity and/or frequency of disease symptoms, eliminating disease symptoms and/or the underlying cause of said symptoms, reducing the frequency or likelihood of disease symptoms and/or their underlying cause, and/or improving or remediating damage caused, directly or indirectly, by disease.
- Beneficial or desired clinical results include, but are not limited to, the reduction in quantity of a disease-causing cell population, such as a population of cancer cells (e.g., CD117+ leukemic cells).
- the terms “variant” and “derivative” are used interchangeably and refer to naturally-occurring, synthetic, and semi-synthetic analogues of a compound, peptide, protein, or other substance described herein.
- a variant or derivative of a compound, peptide, protein, or other substance described herein may retain or improve upon the biological activity of the original material.
- the term “coupling reaction” refers to a chemical reaction in which two or more substituents suitable for reaction with one another react so as to form a chemical moiety that joins (e.g., covalently) the molecular fragments bound to each substituent.
- Coupling reactions include those in which a reactive substituent bound to a fragment that is a cytotoxin, such as a cytotoxin known in the art or described herein, reacts with a suitably reactive substituent bound to a fragment that is an antibody, or antigen-binding fragment thereof, such as an antibody, antigen-binding fragment thereof, or specific anti-CD117 antibody that binds CD117 known in the art or described herein.
- a reactive substituent bound to a fragment that is a cytotoxin such as a cytotoxin known in the art or described herein
- suitably reactive substituents include a nucleophile/electrophile pair (e.g., a thiol/haloalkyl pair, an amine/carbonyl pair, or a thiol/ ⁇ , ⁇ -unsaturated carbonyl pair, among others), a diene/dienophile pair (e.g., an azide/alkyne pair, among others), and the like.
- a nucleophile/electrophile pair e.g., a thiol/haloalkyl pair, an amine/carbonyl pair, or a thiol/ ⁇ , ⁇ -unsaturated carbonyl pair, among others
- diene/dienophile pair e.g., an azide/alkyne pair, among others
- Coupling reactions include, without limitation, thiol alkylation, hydroxyl alkylation, amine alkylation, amine condensation, amidation, esterification, disulfide formation, cycloaddition (e.g., [4+2] Diels-Alder cycloaddition, [3+2] Huisgen cycloaddition, among others), nucleophilic aromatic substitution, electrophilic aromatic substitution, and other reactive modalities known in the art or described herein.
- cycloaddition e.g., [4+2] Diels-Alder cycloaddition, [3+2] Huisgen cycloaddition, among others
- nucleophilic aromatic substitution e.g., [4+2] Diels-Alder cycloaddition, [3+2] Huisgen cycloaddition, among others
- nucleophilic aromatic substitution e.g., [4+2] Diels-Alder cycloa
- R is hydrogen (“aldehyde”), C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 7 carbocyclyl, C 6 -C 20 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl, as defined herein.
- Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryloyl.
- C 1 -C 12 alkyl refers to a straight chain
- Representative C 1 -C 12 alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while branched C 1 -C 12 alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, and 2-methylbutyl.
- a C 1 -C 12 alkyl group can be unsubstituted or substituted.
- alkenyl refers to C 2 -C 12 hydrocarbon containing normal, secondary, or tertiary carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp 2 double bond. Examples include, but are not limited to: ethylene or vinyl, -allyl, -1-butenyl, -2- butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3- dimethyl-2-butenyl, and the like.
- An alkenyl group can be unsubstituted or substituted.
- Alkynyl refers to a C 2 -C 12 hydrocarbon containing normal, secondary, or tertiary carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond. Examples include, but are not limited to acetylenic and propargyl. An alkynyl group can be unsubstituted or substituted.
- Aryl refers to a C 6 -C 20 carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl and anthracenyl. An aryl group can be unsubstituted or substituted.
- Arylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical.
- Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2- phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2- naphthophenylethan-1-yl and the like.
- the arylalkyl group comprises 6 to 20 carbon atoms, e.g.
- Cycloalkyl refers to a saturated carbocyclic radical, which may be mono- or bicyclic. Cycloalkyl groups include a ring having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle.
- Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- a cycloalkyl group can be unsubstituted or substituted.
- Cycloalkenyl refers to an unsaturated carbocyclic radical, which may be mono- or bicyclic. Cycloalkenyl groups include a ring having 3 to 6 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle.
- Examples of monocyclic cycloalkenyl groups include 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1- cyclohex-2-enyl, and 1-cyclohex-3-enyl.
- a cycloalkenyl group can be unsubstituted or substituted.
- Heteroaralkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heteroaryl radical.
- Typical heteroarylalkyl groups include, but are not limited to, 2- benzimidazolylmethyl, 2-furylethyl, and the like.
- the heteroarylalkyl group comprises 6 to 20 carbon atoms, e.g. the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the heteroarylalkyl group is 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S.
- heteroaryl moiety of the heteroarylalkyl group may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), for example: a bicyclo[4,5], [5,5], [5,6], or [6,6] system.
- Heteroaryl and “heterocycloalkyl” as used herein refer to an aromatic or non-aromatic ring system, respectively, in which one or more ring atoms is a heteroatom, e.g. nitrogen, oxygen, and sulfur.
- the heteroaryl or heterocycloalkyl radical comprises 2 to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S.
- a heteroaryl or heterocycloalkyl may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), for example: a bicyclo[4,5], [5,5], [5,6], or [6,6] system.
- Heteroaryl and heterocycloalkyl can be unsubstituted or substituted.
- Heteroaryl and heterocycloalkyl groups are described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.
- heteroaryl groups include by way of example and not limitation pyridyl, thiazolyl, tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carb
- heterocycloalkyls include by way of example and not limitation dihydroypyridyl, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, piperazinyl, quinuclidinyl, and morpholinyl.
- carbon bonded heteroaryls and heterocycloalkyls are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
- carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4- pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
- nitrogen bonded heteroaryls and heterocycloalkyls are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3- pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or beta-carboline.
- nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1- imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
- the foregoing chemical moieties such as “alkyl”, “alkylene”, “heteroalkyl”, “heteroalkylene”, “alkenyl”, “alkenylene”, “heteroalkenyl”, “heteroalkenylene”, “alkynyl”, “alkynylene”, “heteroalkynyl”, “heteroalkynylene”, “cycloalkyl”, “cycloalkylene”, “heterocyclolalkyl”, heterocycloalkylene”, “aryl,” “arylene”, “heteroaryl”, and “heteroarylene” groups can optionally be substituted.
- radical naming conventions can include either a mono- radical or a di-radical, depending on the context.
- a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di- radical.
- a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, and the like.
- radical naming conventions clearly indicate that the radical is a di-radical such as “alkylene,” “alkenylene,” “arylene,” “heterocycloalkylene,” and the like.
- a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated.
- “Isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space.
- stereoisomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”
- stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers,” or sometimes "optical isomers.”
- enantiomers stereoisomers that are non-superimposable mirror images of each other
- enantiomers stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers,” or sometimes “optical isomers.”
- a carbon atom bonded to four non-identical substituents is termed a “chiral center.”
- Chiral isomer means a compound with at least one chiral center.
- a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center.
- Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
- the substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.1966, 5, 385; errata 511; Cahn et al., Angew.
- any compound in this description and in the claims is meant to include both the individual enantiomers, as well as any mixture, racemic or otherwise, of the enantiomers, unless stated otherwise.
- the structure of a compound is depicted as a specific enantiomer, it is to be understood that the coumponds disclosed herein are not limited to that specific enantiomer. Accordingly, enantiomers, optical isomers, and diastereomers of each of the structural formulae of the present disclosure are contemplated herein.
- the structural formula of the compound represents a certain isomer for convenience in some cases, but the present disclosure includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like, it being understood that not all isomers may have the same level of activity.
- the compounds may occur in different tautomeric forms.
- the compounds according to the disclosure are meant to include all tautomeric forms, unless stated otherwise. When the structure of a compound is depicted as a specific tautomer, it is to be understood that the instant disclosure is not limited to that specific tautomer.
- the compounds of any formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable.
- a salt for example, can be formed between an anion and a positively charged group (e.g., amino) on a compound of the disclosure.
- Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).
- a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a compound of the disclosure.
- Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
- Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
- the compounds of the disclosure also include those salts containing quaternary nitrogen atoms.
- suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
- Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
- suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
- the compounds of the present disclosure for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
- Non-limiting examples of hydrates include monohydrates, dihydrates, etc.
- Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.
- solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent.
- Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 O.
- a hydrate refers to, for example, a mono- hydrate, a di-hydrate, a tri-hydrate, etc.
- a crystal polymorphism may be present for the compounds or salts thereof represented by the formulae disclosed herein.
- ADC Anti-CD117 Antibdoy Drug Conjugate
- ADCs Antibody drug conjugates
- ADCs can be administered to a human patient (e.g., a human patient suffering from cancer or a human patient in need of hematopoietic stem cell transplant therapy or gene therapy) for conditioning prior to a cell transplantation.
- a human patient e.g., a human patient suffering from cancer or a human patient in need of hematopoietic stem cell transplant therapy or gene therapy
- doses of the anti-CD117 amatoxin drug conjugate that can be used to condition a human patient or deplete CD117+ cells in a human patient in need thereof.
- the invention provides a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of about 0.05 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- a method of depleting a population of CD117+ cells in a human patient in need thereof comprises administering to the patient a dose of about 0.15 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- a method of depleting a population of CD117+ cells in a human patient in need thereof comprises administering to the patient a dose of about 0.3 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- a method of depleting a population of CD117+ cells in a human patient in need thereof comprises administering to the patient a dose of about 0.5 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- a method of depleting a population of CD117+ cells in a human patient in need thereof comprises administering to the patient a dose of about 1.0 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- a method of depleting a population of CD117+ cells in a human patient in need thereof comprises administering to the patient a dose of about 3.0 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering to the human patient a dose of about 0.15 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of about 0.3 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of about 0.5 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of about 1.0 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of about 3.0 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- the invention provides a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of 0.02 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- a method of depleting a population of CD117+ cells in a human patient in need thereof comprises administering to the patient a dose of 0.04 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- a method of depleting a population of CD117+ cells in a human patient in need thereof comprises administering to the patient a dose of 0.076 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- a method of depleting a population of CD117+ cells in a human patient in need thereof comprises administering to the patient a dose of 0.127 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- a method of depleting a population of CD117+ cells in a human patient in need thereof comprises administering to the patient a dose of 0.19 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- a method of depleting a population of CD117+ cells in a human patient in need thereof comprises administering to the patient a dose of 0.247 mg/kg of an anti-CD117 antibody drug conjugate (ADC), such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- a method of depleting a population of CD117+ cells in a human patient in need thereof comprises administering to the patient a dose of 0.309 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells are depleted.
- ADC anti-CD117 antibody drug conjugate
- a method of depleting a population of CD117+ cells in a human patient in need thereof comprises administering to the patient a dose of 0.386 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- a method of depleting a population of CD117+ cells in a human patient in need thereof comprises administering to the patient a dose of 0.483 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- a depleting a population of CD117+ cells in a human patient in need thereof comprises administering to the patient a dose of 0.603 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- a depleting a population of CD117+ cells in a human patient in need thereof comprises administering to the patient a dose of 0.754 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- a depleting a population of CD117+ cells in a human patient in need thereof comprises administering to the patient a dose of 0.942 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering to the human patient a dose of 0.02 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.04 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.076 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.127 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.190 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.247 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.2 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.309 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.3 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.386 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.483 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- HSC hematopoietic stem cell
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.4 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.603 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.6 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- ADC anti-CD117 antibody drug conjugate
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.754 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- HSC hematopoietic stem cell
- a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.942 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
- the invention provides a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of 0.02 mg/kg of an anti-CD117 ADC, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- a method of depleting a population of CD117+ cells in a human patient in need thereof comprising administering to the patient a dose of 0.04 mg/kg of an anti-CD117 ADC, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- a method of depleting a population of CD117+ cells in a human patient in need thereof wherein the method comprises administering to the patient a dose of 0.08 mg/kg of an anti-CD117 ADC, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- a method of depleting a population of CD117+ cells in a human patient in need thereof comprising administering to the patient a dose of 0.13 mg/kg of an anti-CD117 ADC, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- the method comprises administering to the patient a dose of 0.19 mg/kg of an anti-CD117 ADC, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
- a method of conditioning a human patient for a hematopoietic stem cell (HSC) transplant comprising administering to the human patient a dose of 0.02 mg/kg of MGTA-117 such that the human patient is conditioned for an HSC transplant.
- a method of conditioning a human patient for a hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.04 mg/kg of an anti-CD117 ADC such that the human patient is conditioned for an HSC transplant.
- a method of conditioning a human patient for a hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.08 mg/kg of an anti-CD117 ADC such that the human patient is conditioned for an HSC transplant.
- a method of conditioning a human patient for a hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.13 mg/kg of an anti-CD117 ADC such that the human patient is conditioned for an HSC transplant.
- a method of conditioning a human patient for a hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.19 mg/kg of an anti-CD117 ADC such that the human patient is conditioned for an HSC transplant.
- HSCs hematopoietic stem cells
- the methods disclosed herein represent targeted conditioning, whereby an anti- CD117 ADC is used to selectively deplete hematopoietic stem cells (HSCs) in a human patient in need of an HSC transplant.
- HSCs hematopoietic stem cells
- MGTA-117 to specifically target CD117+ HSCs allows for conditioning without the need for myeloablative regimens, such as high-dose or high-intensity chemotherapeutic agents.
- the methods disclosed herein potentially eliminate the need for chemotherapeutic agents altogether.
- a hematopoietic stem cell (HSC) transplant can be administered to a subject in need of treatment so as to populate or re-populate one or more blood cell types.
- HSCs generally exhibit multi-potency, and can thus differentiate into multiple different blood lineages including, but not limited to, granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), erythrocytes (e.g., reticulocytes, erythrocytes), thrombocytes (e.g., megakaryoblasts, platelet producing megakaryocytes, platelets), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B-cells and T-cells).
- granulocytes e.g., promyelocytes, neutrophils, eosinophils, basophils
- erythrocytes e.g., reticulocytes, erythrocytes
- thrombocytes e.g., megakaryoblast
- HSCs are additionally capable of self-renewal, and can thus give rise to daughter cells that have equivalent potential as the mother cell, and also feature the capacity to be reintroduced into a transplant recipient whereupon they home to the hematopoietic stem cell niche and re-establish productive and sustained hematopoiesis.
- Hematopoietic stem cells can thus be administered to a patient defective or deficient in one or more cell types of the hematopoietic lineage in order to re-constitute the defective or deficient population of cells in vivo, thereby treating the pathology associated with the defect or depletion in the endogenous blood cell population.
- compositions and methods described herein can thus be used to treat a non-malignant hemoglobinopathy (e.g., a hemoglobinopathy such as sickle cell anemia, thalassemia, Fanconi anemia, aplastic anemia, and Wiskott-Aldrich syndrome). Additionally or alternatively, the compositions and methods described herein can be used to treat an immunodeficiency, such as a congenital immunodeficiency. Additionally or alternatively, the compositions and methods described herein can be used to treat a malignancy or proliferative disorder, such as a hematologic cancer or myeloproliferative disease.
- a non-malignant hemoglobinopathy e.g., a hemoglobinopathy such as sickle cell anemia, thalassemia, Fanconi anemia, aplastic anemia, and Wiskott-Aldrich syndrome.
- an immunodeficiency such as a congenital immunodeficiency
- compositions and methods described herein may be administered to a patient so as to deplete a population of endogenous hematopoietic stem cells prior to hematopoietic stem cell transplantation therapy, in which case the transplanted cells can home to a niche created by the endogenous cell depletion step and establish productive hematopoiesis. This, in turn, can re-constitute a population of cells depleted during cancer cell eradication, such as during systemic chemotherapy.
- Exemplary hematological cancers that can be treated using the compositions and methods described herein include, without limitation, acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, multiple myeloma, diffuse large B-cell lymphoma, and non-Hodgkin’s lymphoma, as well as other cancerous conditions, including neuroblastoma.
- the methods disclosed herein can be used to treat cancers directly, such as cancers characterized by cells that are CD117+.
- MGTA-117 can be used to treat leukemia, particularly in patients that exhibit CD117+ leukemic cells.
- CD117+ cancerous cells such as leukemic cells
- the compositions and methods described herein can be used to treat various cancers directly.
- Exemplary cancers that may be treated in this fashion include hematological cancers, such as acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, multiple myeloma, diffuse large B-cell lymphoma, and non-Hodgkin’s lymphoma.
- Methods for the depletion of CD117+ cells are further described in WO 2 017/219029, which is hereby incorporated by reference in its entirety.
- the methods disclosed herein may be used to selectively deplete CD117-positive cells in a human patient having acute AML or myelodysplasia-excess blasts (MDS-EB).
- the AML is CD117+ AML or the MDS-EB is MDS-EB with 5% to 19% marrow myeloblasts and/or 2% to 19% peripheral blasts for MDS-EB.
- the MDS-EB is CD117+ MDS-EB.
- the human patient may be an adult, e.g., age 18 to 75. The human patient may have failed previous therapy prior to administration of an anti- CD117 ADC for selective depletion of CD117+ HSCs.
- the human patient may have acute AML and may have previously failed primary AML induction.
- the human patient may have MDS-EB and have previously failed or be refractory to HMA.
- HSCs transplanted into a subject in need thereof may be obtained from the patient themselves (i.e., autologous) or a donor (e.g., allogeneic).
- HSC donors include a related donor, an unrelated donor, a haplo-identical transplant donor, or an umbilical blood donor.
- allogeneic when used in the context of transplantation, is used to define cells (or tissue or an organ) that are transplanted from a donor to a recipient of the same species but who is genetically different.
- allogeneic cells refers to cell types that are genetically distinct between two individuals, yet belong to the same species, e.g., human.
- the term “allogeneic” is used to define cells, such as stem cells, that are transplanted from a donor to an unrelated recipient of the same species.
- autologous refers to cells or a graft where the donor and recipient are the same subject.
- the HSCs transplanted to the human subject following administration of an anti-CD117 ADC are autologous but are genetically modified, e.g., modified to correct a gene mutation that results in a disease, e.g., sickle cell anemia.
- a human patient who is administered MGTA-117 in accordance with the methods disclosed herein has an Eastern Cooperative Oncology Group (ECOG) performance status of ⁇ 2; has an adequate baseline hepatic function (e.g., alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ⁇ 2 x upper limit of normal (ULN), and serum bilirubin ⁇ 1.5 x ULN); has an estimated creatinine clearance ⁇ 60 mL/min; and/or has adequate cardiac function as demonstrated by cardiac left ventricular ejection fraction ⁇ 40%.
- EOG Eastern Cooperative Oncology Group
- NCI National Cancer Institute
- CCAE Common Terminology Criteria for Adverse Events
- a human patient who is administered MGTA-117 in accordance with the methods disclosed herein does not have acute promyelocytic leukemia (APL); does not have a known active central nervous system (CNS) leukemia or chloroma (granulocyte sarcoma); has not received HSCT within 6 months of administration of MGTA-117; has not received chimeric antigen-receptor cell therapies within 6 months prior to dosing; does not have active graft-versus-host disease (GVHD); does not have active hepatitis B (Hep-B) or hepatitis C (Hep-C) infection or a history of human immunodeficiency virus (HIV); does not have a QTc value >470 msec; has not received another investigational drug or device within 30 days of administration of MGTA-117; does not have any clinically significant medical condition; does not have active uncontrolled systemic bacterial, fungal, or viral infection; does not have a history of serious allergic reactions; has not
- compositions and methods described herein can be used to treat cancers, such as cancers characterized by cells that are CD117+.
- the compositions and methods described herein can be used to treat leukemia, particularly in patients that exhibit CD117+ leukemic cells.
- the compositions and methods described herein can be used to treat various cancers directly.
- Exemplary cancers that may be treated in this fashion include hematological cancers, such as acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, multiple myeloma, diffuse large B-cell lymphoma, and non-Hodgkin's lymphoma.
- the cancer is a hematological cancer.
- Acute myeloid leukemia is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that build up in the bone marrow and interfere with the production of normal blood cells.
- AML is the most common acute leukemia affecting adults, and its incidence increases with age.
- the symptoms of AML are caused by replacement of normal bone marrow with leukemic cells, which causes a drop in red blood cells, platelets, and normal white blood cells.
- the anti- CD117 ADCs described herein are used to treat AML in a human patient in need thereof.
- the anti-CD117 ADC treatment depletes AML cells in the treated subjects. In some embodiments 50% or more of the AML cells are depleted. In other embodiments, 60% or more of the AML cells are depleted, or 70% or more of the AML cells are depleted, or 80% of more or 90% or more, or 95% or more of the AML cells are depleted.
- the methods disclosed herein are useful for treating a human subject having a hematological cancer, such as leukemia or myelodysplastic syndrome. Examples of leukemia that may be treated using the methods and compositions disclosed herein include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, or chronic lymphocytic leukemia.
- hematopoietic stem cell transplant therapy can be administered to a subject in need of treatment so as to populate or re-populate one or more blood cell types.
- Hematopoietic stem cells generally exhibit multi-potency, and can thus differentiate into multiple different blood lineages including, but not limited to, granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), erythrocytes (e.g., reticulocytes, erythrocytes), thrombocytes (e.g., megakaryoblasts, platelet producing megakaryocytes, platelets), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B-cells and T-cells).
- granulocytes e.g., promyelocytes, neutrophils, eosinophils,
- Hematopoietic stem cells are additionally capable of self-renewal, and can thus give rise to daughter cells that have equivalent potential as the mother cell, and also feature the capacity to be reintroduced into a transplant recipient whereupon they home to the hematopoietic stem cell niche and re-establish productive and sustained hematopoiesis. Hematopoietic stem cells can thus be administered to a patient defective or deficient in one or more cell types of the hematopoietic lineage in order to re-constitute the defective or deficient population of cells in vivo, thereby treating the pathology associated with the defect or depletion in the endogenous blood cell population.
- compositions and methods described herein can thus be used to treat a non-malignant hemoglobinopathy (e.g., a hemoglobinopathy selected from the group consisting of sickle cell anemia, thalassemia, Fanconi anemia, aplastic anemia, and Wiskott-Aldrich syndrome). Additionally or alternatively, the compositions and methods described herein can be used to treat an immunodeficiency, such as a congenital immunodeficiency. Additionally or alternatively, the compositions and methods described herein can be used to treat an acquired immunodeficiency (e.g., an acquired immunodeficiency selected from the group consisting of HIV and AIDS).
- a non-malignant hemoglobinopathy e.g., a hemoglobinopathy selected from the group consisting of sickle cell anemia, thalassemia, Fanconi anemia, aplastic anemia, and Wiskott-Aldrich syndrome.
- an immunodeficiency such as a congenital immunodeficiency.
- compositions and methods described herein can be used to treat a metabolic disorder (e.g., a metabolic disorder selected from the group consisting of glycogen storage diseases, mucopolysaccharidoses, Gaucher's Disease, Hurlers Disease, sphingolipidoses, and metachromatic leukodystrophy).
- a metabolic disorder e.g., a metabolic disorder selected from the group consisting of glycogen storage diseases, mucopolysaccharidoses, Gaucher's Disease, Hurlers Disease, sphingolipidoses, and metachromatic leukodystrophy.
- Additional diseases that can be treated with the compositions and methods described herein include, without limitation, lysosomal disorders, such as Gaucher disease, Krabbe disease, Metachromatic leukodystrophy (MLD), Mucopolysaccharidosis (MPS), Niemann-Pick disease, and Tay-Sachs disease.
- the transplanted cells are genetically modified in a manner to treat or cure the disease, a hemoglobinapathy or a lysosomal disease.
- Other diseases and conditions that can be treated using the methods disclosed herein are provided in U.S. Patent No.10,899,843, which is incorporated by reference herein.
- Anti-CD117 ADCs described herein can be administered to a patient (e.g., a human patient suffering from cancer, an autoimmune disease, or in need of hematopoietic stem cell transplant therapy) in a variety of dosage forms.
- anti-CD117 antibodies, antigen-binding fragments thereof, or ADCs described herein can be administered to a patient suffering from cancer, an autoimmune disease, or in need of hematopoietic stem cell transplant therapy in the form of an aqueous solution, such as an aqueous solution containing one or more pharmaceutically acceptable excipients.
- the aqueous solution may be sterilized using techniques known in the art.
- a physician of skill in the art can administer to a human patient in need of hematopoietic stem cell transplant therapy an anti-CD117 ADC capable of binding CD117 expressed by hematopoietic stem cells.
- a population of endogenous hematopoietic stem cells can be depleted prior to administration of an exogenous hematopoietic stem cell graft so as to promote engraftment of the hematopoietic stem cell graft.
- the anti-CD117 ADC can s be administered to the patient, for example, by intravenous administration, prior to transplantation of exogenous hematopoietic stem cells (such as autologous, syngeneic, or allogeneic hematopoietic stem cells) to the patient.
- the patient may then receive an infusion (e.g., an intravenous infusion) of exogenous hematopoietic stem cells, such as from the same physician that performed the conditioning therapy or from a different physician.
- an infusion e.g., an intravenous infusion
- the physician may administer the patient an infusion of autologous, syngeneic, or allogeneic hematopoietic stem cells, for instance, at a dosage of from 1 x 10 3 to 1 x 10 9 hematopoietic stem cells/kg.
- the physician may monitor the engraftment of the hematopoietic stem cell transplant, for example, by withdrawing a blood sample from the patient and determining the increase in concentration of hematopoietic stem cells or cells of the hematopoietic lineage (such as megakaryocytes, thrombocytes, platelets, erythrocytes, mast cells, myeloblasts, basophils, neutrophils, eosinophils, microglia, granulocytes, monocytes, osteoclasts, antigen-presenting cells, macrophages, dendritic cells, natural killer cells, T-lymphocytes, and B-lymphocytes) following administration of the transplant.
- hematopoietic stem cells or cells of the hematopoietic lineage such as megakaryocytes, thrombocytes, platelets, erythrocytes, mast cells, myeloblasts, basophils, neutrophils, eosinophils, microgli
- This analysis may be conducted, for example, from about 1 hour to about 6 months, or more, following hematopoietic stem cell transplant therapy (e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, or more).
- a finding that the concentration of hematopoietic stem cells or cells of the hematopoietic lineage has increased (e.g., by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 500%, or more) following the transplant therapy relative to the concentration of the corresponding cell type prior to transplant therapy provides one indication that treatment with the anti-CD117 antibody, an antigen-binding fragment thereof, or an ADC has successfully promoted engraftment of the transplanted hematopoietic stem cell graft.
- Engraftment of hematopoietic stem cell transplants due to the administration of an anti- CD117 antibody, or antigen-binding fragments thereof, or ADCs, can manifest in a variety of empirical measurements. For instance, engraftment of transplanted hematopoietic stem cells can be evaluated by assessing the quantity of competitive repopulating units (CRU) present within the bone marrow of a patient following administration of an antibody or antigen-binding fragment thereof capable of binding capable of binding an antigen expressed by hematopoietic stem cells (e.g., CD117 (e.g., GNNK+ CD117) and subsequent administration of a hematopoietic stem cell transplant.
- CRU competitive repopulating units
- a reporter gene such as an enzyme that catalyzes a chemical reaction yielding a fluorescent, chromophoric, or luminescent product
- FACS fluorescence activated cell sorting
- Engraftment can also be determined by measuring white blood cell counts in peripheral blood during a post-transplant period, and/or by measuring recovery of marrow cells by donor cells in a bone marrow aspirate sample. Engraftment of hematopoietic stem cell transplants due to the administration of an anti- CD117 ADC described herein can manifest in a variety of empirical measurements. For instance, engraftment of transplanted hematopoietic stem cells can be evaluated by assessing the quantity of competitive repopulating units (CRU) present within the bone marrow of a patient following administration of an antibody or antigen-binding fragment thereof capable of binding an antigen described herein and subsequent administration of a hematopoietic stem cell transplant.
- CRU competitive repopulating units
- a reporter gene such as an enzyme that catalyzes a chemical reaction yielding a fluorescent, chromophoric, or luminescent product
- FACS fluorescence activated cell sorting
- Engraftment can also be determined by measuring white blood cell counts in peripheral blood during a post- transplant period, and/or by measuring recovery of marrow cells by donor cells in a bone marrow aspirate sample.
- the present invention includes dosing regimens that reduce adverse events and toxicity using ADCs that are capable of binding CD117 expressed by, e.g., an HSC.
- the sections that follow provide a description of anti-CD117 ADCs that can be administered to a patient in need of a transplantation, e.g., hematopoietic stem cell transplant, in order to promote engraftment of hematopoietic stem cells, as well as methods of administering such therapeutics to a patient prior to hematopoietic stem cell transplantation.
- an anti-CD117 antibody, or antigen binding fragment thereof comprises a heavy chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 3, 4, and 5, respectively, and comprises a light chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 6, 7, and 8, respectively.
- an anti-CD117 antibody, or antigen binding fragment thereof comprises a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 2, and a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 1.
- the heavy chain variable region (VH) amino acid sequence of Ab85 is provided below as SEQ ID NO: 1.
- the VH CDR amino acid sequences of Ab85 are underlined below and are as follows: NYWIG (VH CDR1; SEQ ID NO: 3); IINPRDSDTRYRPSFQG (VH CDR2; SEQ ID NO: 4); and HGRGYEGYEGAFDI (VH CDR3; SEQ ID NO: 5).
- Ab85 VH sequence (SEQ ID NO: 1)
- the light chain variable region (VL) amino acid sequence of Ab85 is provided below as SEQ ID NO: 2.
- the VL CDR amino acid sequences of Ab85 are underlined below and are as follows: RSSQGIRSDLG (VL CDR1; SEQ ID NO: 6); DASNLET (VL CDR2; SEQ ID NO: 7); and QQANGFPLT (VL CDR3; SEQ ID NO: 8).
- Ab85 VL sequence (SEQ ID NO: 2)
- an anti-CD117 antibody, or antigen binding fragment thereof comprises a heavy chain having the amino acid sequence as set forth as SEQ ID NO: 9, and a light chain having an amino acid sequence set forth as SEQ ID NO: 10.
- an anti-CD117 antibody is an IgG1 isotype.
- the anti-CD117 antibody comprising any of the sequences set forth in the Table below can be an intact antibody and/or an IgG1 or an IgG4 isotype.
- the anti-CD117 antibody, or binding fragment thereof comprises a variant Fc region, wherein said variant Fc region comprises at least one amino acid modification relative to a wild-type Fc region, such that said molecule has an altered affinity for an FcgammaR. Certain amino acid positions within the Fc region are known through crystallography studies to make a direct contact with Fc ⁇ R.
- an anti-CD117 antibody described herein comprises an Fc region comprising an amino acid substituion at L234 and/or L235, e.g., L234A and L235A (EU index).
- the anti-CD117 antibodies described herein may comprise variant Fc regions comprising modification of at least one residue that makes a direct contact with an Fc ⁇ R based on structural and crystallographic analysis.
- the Fc region of the anti-CD117 antibody (or Fc containing fragment thereof) comprises an amino acid substitution at amino acid 265 according to the EU index as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, NH1, MD (1991), expressly incorporated herein by references.
- the "EU index as in Kabat” or “EU index” refers to the numbering of the human IgG1 EU antibody and is used herein in reference to Fc amino acid positions unless otherwise indicated.
- the Fc region comprises a D265A mutation. In one embodiment, the Fc region comprises a D265C mutation. In some embodiments, the Fc region of the anti-CD117 antibody (or fragment thereof) comprises an amino acid substitution at amino acid 234 according to the EU index as in Kabat. In one embodiment, the Fc region comprises a L234A mutation. In some embodiments, the Fc region of the anti-CD117 antibody (or fragment thereof) comprises an amino acid substitution at amino acid 235 according to the EU index as in Kabat. In one embodiment, the Fc region comprises a L235A mutation. In yet another embodiment, the Fc region comprises a L234A and L235A mutation.
- the Fc region comprises a D265C, L234A, and L235A mutation.
- a variant IgG Fc domain comprises one or more amino acid substitutions resulting in decreased or ablated binding affinity for an FcgammaR and/or C1q as compared to the wild-type Fc domain not comprising the one or more amino acid substitutions.
- Fc binding interactions are essential for a variety of effector functions and downstream signaling events including, but not limited to, antibody dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC).
- an antibody comprising a modified Fc region (e.g., comprising a L234A, L235A, and a D265C mutation) has substantially reduced or abolished effector functions.
- Affinity to an Fc region can be determined using a variety of techniques known in the art, for example but not limited to, equilibrium methods (e.g., enzyme-linked immunoabsorbent assay (ELISA); KinExA, Rathanaswami et al.
- binding affinities and kinetics can be found in Paul, W. E., ed., Fundamental Immunology, 4th Ed., Lippincott-Raven, Philadelphia (1999), which focuses on antibody-immunogen interactions.
- a competitive binding assay is a radioimmunoassay comprising the incubation of labeled antigen with the antibody of interest in the presence of increasing amounts of unlabeled antigen, and the detection of the antibody bound to the labeled antigen.
- the affinity of the antibody of interest for a particular antigen and the binding off-rates can be determined from the data by scatchard plot analysis. Competition with a second antibody can also be determined using radioimmunoassays.
- an anti-CD117 antibody described herein comprises an Fc region comprising L235A, L235A, and D265C (EU index).
- the antibodies of the invention may be further engineered to further modulate antibody half-life by introducing additional Fc mutations, such as those described for example in (Dall'Acqua et al. (2006) J Biol Chem 281: 23514-24), (Zalevsky et al. (2010) Nat Biotechnol 28: 157-9), (Hinton et al. (2004) J Biol Chem 279: 6213- 6), (Hinton et al.
- the Fc region comprises a mutation resulting in a decrease in half life.
- An antibody having a short half-life may be advantageous in certain instances where the antibody is expected to function as a short-lived therapeutic, e.g., the conditioning step described herein where the antibody is administered followed by HSCs.
- the antibody would be substantially cleared prior to delivery of the HSCs, which also generally express CD117 but are not the target of the anti-CD117 antibody, unlike the endogenous stem cells.
- the Fc region comprises a mutation at position 435 (EU index according to Kabat).
- the mutation is an H435A mutation.
- the anti-CD117 antibody or ADC described herein has a half-life of equal to or less than 24 hours, equal to or less than 22 hours, equal to or less than 20 hours, equal to or less than 18 hours, equal to or less than 16 hours, equal to or less than 14 hours, equal to or less than 13 hours, equal to or less than 12 hours, or equal to or less than 11 hours.
- the half-life of the antibody is 11 hours to 24 hours; 12 hours to 22 hours; 10 hours to 20 hours; 8 hours to 18 hours; or 14 hours to 24 hours.
- Antibodies may be produced using recombinant methods and compositions, e.g., as described in U.S. Pat. No.4,816,567.
- isolated nucleic acid encoding an anti-CD117 antibody described herein is provided.
- Such nucleic acid may encode an amino acid sequence comprising the VL and/or an amino acid sequence comprising the VH of the antibody (e.g., the light and/or heavy chains of the antibody).
- one or more vectors e.g., expression vectors comprising such nucleic acid are provided.
- a host cell comprising such nucleic acid.
- a host cell comprises (e.g., has been transformed with): (1) a vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody, or (2) a first vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising the VH of the antibody.
- the host cell is eukaryotic, e.g.
- a method of making an anti- CLL-1 antibody comprises culturing a host cell comprising a nucleic acid encoding the antibody, as provided above, under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).
- nucleic acid encoding an antibody e.g., as described above, is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell.
- Such nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody).
- Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein.
- antibodies may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed.
- For expression of antibody fragments and polypeptides in bacteria see, e.g., U.S. Pat. Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (B.K.C.
- the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.
- Vertebrate cells may also be used as hosts.
- mammalian cell lines that are adapted to grow in suspension may be useful.
- Other examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J.
- TM4 cells as described, e.g., in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N.Y. Acad. Sci.383:44-68 (1982); MRC 5 cells; and FS4 cells.
- CHO Chinese hamster ovary
- DHFR- CHO cells Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)
- myeloma cell lines such as Y0, NS0 and Sp2/0.
- Yazaki and Wu Methods in Molecular Biology, Vol.248 (B. K. C. Lo, ed., Humana Press, Totowa, N.J.), pp. 255-268 (2003).
- the anti-CD117 antibody, or antigen binding fragment thereof comprises variable regions having an amino acid sequence that is at least 95%, 96%, 97% or 99% identical to the SEQ ID Nos disclosed herein.
- the anti-CD117 antibody, or antigen binding fragment thereof comprises CDRs comprising the SEQ ID Nos disclosed herein with framework regions of the variable regions described herein having an amino acid sequence that is at least 95%, 96%, 97% or 99% identical to the SEQ ID Nos disclosed in the Tables herein. TABLE 1: ANTI-CD117 ANTIBODY SEQUENCES
- Anti-CD117 Antibody Drug Conjugates Anti-CD117 antibodies, and antigen-binding fragments thereof, described herein, e.g., Ab85, can be conjugated (linked) to a cytotoxin, i.e., an amatoxin.
- the cytotoxic molecule is conjugated to a cell internalizing anti-CD117 antibody, or antigen-binding fragment thereof as disclosed herein such that following the cellular uptake of the antibody, or fragment thereof, the cytotoxin may access its intracellular target and mediate hematopoietic cell death.
- An example of such an antibody is Ab85.
- ADCs of the present invention therefore may be of the general formula Ab-(Z-L-D) n , wherein an anti-CD117 antibody or antigen-binding fragment thereof (Ab) is conjugated (covalently linked) to a linker (L), and through a chemical moiety (Z), to a cytotoxic moiety (“drug,” D) which is an amatoxin.
- the anti-CD117 antibody may be conjugated to a number of drug moieties as indicated by integer n, which represents the average number of amatoxins per antibody. Any number of amatoxins can be conjugated to the antibody, e.g., about 1, about 2, about 3, about 4, about 5, about 6, about 7, or about 8. In some embodiments, n is from 1 to 4.
- n is from 1 to 3. In some embodiments, n is about 2. In some embodiments, n is about 1.
- two amatoxins are conjugated to an anti-CD117 antibody.
- two amatoxins can be conjugated to an anti-CD117 antibody via cysteine residues in the Fc region of the anti-CD117 antibody.
- the average number of drug moieties per antibody in preparations of ADC from conjugation reactions may be characterized by conventional means such as mass spectroscopy, ELISA assay, and HPLC. The quantitative distribution of ADC in terms of n may also be determined.
- n may be limited by the number of attachment sites on the antibody.
- an antibody may have only one or several cysteine thiol groups, or may have only one or several sufficiently reactive thiol groups through which a linker may be attached.
- antibodies do not contain many free and reactive cysteine thiol groups which may be linked to a drug moiety; primarily, cysteine thiol residues in antibodies exist as disulfide bridges.
- an antibody may be reduced with a reducing agent such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP), under partial or total reducing conditions, to generate reactive cysteine thiol groups.
- a reducing agent such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP)
- higher drug loading e.g., n>5
- fewer than the theoretical maximum number of drug moieties are conjugated to an antibody during a conjugation reaction.
- An antibody may contain, for example, lysine residues that do not react with the drug-linker intermediate or linker reagent, as discussed below.
- an antibody is subjected to denaturing conditions to reveal reactive nucleophilic groups such as lysine or cysteine.
- the loading (drug/antibody ratio) of an ADC may be controlled in different ways, e.g., by: (i) limiting the molar excess of drug-linker intermediate or linker reagent relative to antibody, (ii) limiting the conjugation reaction time or temperature, (iii) partial or limiting reductive conditions for cysteine thiol modification, (iv) engineering by recombinant techniques the amino acid sequence of the antibody such that the number and position of cysteine residues is modified for control of the number and/or position of linker-drug attachments.
- Amatoxins Described herein are uses of anti-CD117 antibody drug conjugates comprising an anti- CD117 anitbody conjugated to an amatoxin.
- Amatoxins useful in conjunction with the compositions and methods described herein include compounds according to, but are not limited to, formula (I), (I) wherein: R 1 is H, OH, or OR A ; R 2 is H, OH, or OR B ; R A and R B , when present, together with the oxygen atoms to which they are bound, combine to form an optionally substituted 5-membered heterocycloalkyl group; R 3 is H or R D ; R 4 is H, OH, ORD, or RD; R 5 is H, OH, ORD, or RD; R 6 is H, OH, ORD, or RD; R 7 is H, OH, ORD, or RD; R 8 is OH, NH 2 , or ORD; R 9 is H, OH, or ORD; X is -S-, -S(O
- amatoxins useful in conjunction with the compositions and methods described herein include compounds according to formula (Ia) (Ia), wherein R 4 , R 5 , X, and R 8 are each as defined above.
- amatoxins useful in conjunction with the compositions and methods described herein include compounds according to formula (Ib), below: (Ib) wherein: R 1 is H, OH, or OR A ; R 2 is H, OH, or OR B ; R A and R B , when present, together with the oxygen atoms to which they are bound, combine to form an optionally substituted 5-membered heterocycloalkyl group; R 3 is H or R D ; R 4 is H, OH, ORD, or RD; R 5 is H, OH, OR D , or R D ; R 6 is H, OH, OR D , or R D ; R 7 is H, OH, OR D , or R D ; R 8 is OH, NH 2 , or OR D
- amatoxins useful in conjunction with the compositions and methods described herein also include compounds according to formula (Ic), below: (Ic) wherein: R 1 is H, OH, or OR A ; R 2 is H, OH, or OR B ; R A and R B , when present, together with the oxygen atoms to which they are bound, combine to form an optionally substituted 5-membered heterocycloalkyl group; R 3 is H or R D ; R 4 is H, OH, OR D , or R D ; R 5 is H, OH, OR D , or R D ; R 6 is H, OH, OR D , or R D ; R 7 is H, OH, OR D , or R D ; R 8 is OH, NH 2 , or OR D ; R 9 is H, OH, or OR D ; X is -S-, -S(O)-, or -SO 2 -; and RD is optionally substituted alkyl (e.g., C
- the cytotoxin in the ADC is an amatoxin or derivative thereof according to formula (I, Ia, Ib, or Ic).
- the ADC is represented by the general formula Ab-Z-L-Am, wherein Ab is an antibody or antigen-binding fragment thereof that binds CD117, L is a linker, Z is a chemical moiety, and Am is an amatoxin.
- the ADC having the general formula Ab-Z-L-Am is represented by formula (II): (II) wherein: R 1 is H, OH, OR A , or OR C ; R 2 is H, OH, OR B , or OR C ; R A and R B , when present, together with the oxygen atoms to which they are bound, combine to form a 5-membered heterocycloalkyl group; R 3 is H, R C , or R D ; R 4 is H, OH, OR C , OR D , R C , or R D ; R 5 is H, OH, ORC, ORD, RC, or RD; R 6 is H, OH, ORC, ORD, RC, or RD; R 7 is H, OH, ORC, ORD, RC, or RD; R 8 is OH, NH 2 , ORC, ORD, NHRC, or NRCRD; R 9 is H, OH, ORC, or ORD; X
- Am contains exactly one R C substituent.
- the cytotoxin is an amatoxin or derivative thereof and the ADC Ab-Z-L-Am is represented by formula (II), wherein: R 1 and R 2 are each independently H or OH; R 3 is RC; R 4 , R 6 , and R 7 are each H; R 5 is H, OH, or OC 1 -C 6 alkyl; R 8 is OH or NH 2 ; R 9 is H or OH; X is -S-, -S(O)-, or -SO 2 -; and RC and RD are as defined above.
- amatoxin-linker conjugates are described, for example, in U.S.
- the cytotoxin is an amatoxin or derivative thereof and the ADC Ab-Z-L-Am is represented by formula (II), wherein: R 1 and R 2 are each independently H or OH; R 3 , R 6 , and R 7 are each H; R 4 and R 5 are each independently H, OH, ORC, or RC; R 8 is OH or NH 2 ; R9 is H or OH; X is -S-, -S(O)-, or -SO 2 -; and RC and RD are as defined above.
- amatoxin-linker conjugates are described, for example, in U.S.
- the cytotoxin is an amatoxin or derivative thereof and the ADC Ab-Z-L-Am is represented by formula (II), wherein: R 1 and R 2 are each independently H or OH; R 3 , R 6 , and R 7 are each H; R 4 and R 5 are each independently H or OH; R 8 is OH, NH 2 , OR C , or NHR C ; R 9 is H or OH; X is -S-, -S(O)-, or -SO 2 -; and R C and R D are as defined above.
- formula (II) wherein: R 1 and R 2 are each independently H or OH; R 3 , R 6 , and R 7 are each H; R 4 and R 5 are each independently H or OH; R 8 is OH, NH 2 , OR C , or NHR C ; R 9 is H or OH; X is -S-, -S(O)-, or -SO 2 -; and R C and R D are as
- amatoxin conjugates are described, for example, in U.S. Patent Nos.9,233,173 and 9,399,681, the disclosures of each of which are incorporated herein by reference in their entirety.
- the CD117 antibodies, or antigen-binding fragments, described herein may be bound to an amatoxin so as to form an ADC represented by the formula Ab-Z-L- Am, wherein Ab is the CD117 antibody, or antigen-binding fragment thereof, L is a linker, Z is a chemical moiety and Am is an amatoxin, each as described herein.
- the anti-CD117 ADC has the structure of formula (III): (III), wherein: X is S or –S(O)-; L is a linker; Z is a chemical moiety formed by a coupling reaction between a reactive substituent present on L and a reactive substituent present within the anti-CD117 antibody; and Ab is the anti-CD117 antibody.
- L is a non-cleavable linker;
- an anti-CD117 ADC described herein has the structure of formula (IIIa):
- the anti-CD117 ADC has the structure of formula (IV):
- the anti-CD117 ADC has the structure of formula (IVa): (IVa) a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Ab is the anti-CD117 antibody.
- the anti-CD117 ADC has the structure of formula (IVb):
- Amatoxins that may be used in the ADCs described herein are also provided in WO 2020/216947, which is incorporated by reference herein.
- Linkers A variety of linkers can be used to conjugate antibodies, or antigen-binding fragments, as described herein (e.g., antibodies, or antigen-binding fragments thereof, that recognize and bind CD117 (such as GNNK+ CD117) with a cytotoxic molecule, i.e., amatoxin.
- Linker means a divalent chemical moiety comprising a covalent bond or a chain of atoms that covalently attaches an anti-CD117 antibody or fragment thereof (Ab) to a drug moiety (D) to form antibody-drug conjugates (ADC) of formula II.
- Suitable linkers have two reactive termini, one for conjugation to an antibody and the other for conjugation to a cytotoxin.
- the antibody conjugation reactive terminus of the linker is typically a site that is capable of conjugation to the antibody through a cysteine thiol or lysine amine group on the antibody, and so is typically a thiol-reactive group such as a double bond (as in maleimide) or a leaving group such as a chloro, bromo, iodo, or an R- sulfanyl group, or an amine-reactive group such as a carboxyl group; while the cytotoxin conjugation reactive terminus of the linker is typically a site that is capable of conjugation to the cytotoxin.
- Non-limiting examples for linker-cytotoxin conjugation include, for example, formation of an amide bond with a basic amine or carboxyl group on the cytotoxin, via a carboxyl or basic amine group on the linker, respectively, or formation of an ether or the like, via alkylation of an OH group on the cytotoxin, via e.g., a leaving group on the linker.
- cytotoxin-linker conjugation is through formation of an amide bond with a basic amine or carboxyl group on the cytotoxin, and so the reactive substituent on the linker is respectively a carboxyl or basic amine group.
- linker When the term "linker" is used in describing the linker in conjugated form, one or both of the reactive termini will be absent (such as reactive moiety Z′, having been converted to chemical moiety Z) or incomplete (such as being only the carbonyl of the carboxylic acid) because of the formation of the bonds between the linker and/or the cytotoxin, and between the linker and/or the antibody or antigen-binding fragment thereof. Such conjugation reactions are described further herein below.
- the linker is cleavable under intracellular conditions, such that cleavage of the linker releases the drug unit from the antibody in the intracellular environment.
- the linker unit is not cleavable and the drug is released, for example, by antibody degradation.
- the linkers useful for the present ADCs are preferably stable extracellularly, prevent aggregation of ADC molecules and keep the ADC freely soluble in aqueous media and in a monomeric state.
- the ADC Before transport or delivery into a cell, the ADC is preferably stable and remains intact, i.e. the antibody remains linked to the drug moiety.
- the linkers are stable outside the target cell and may be cleaved at some efficacious rate inside the cell.
- An effective linker will: (i) maintain the specific binding properties of the antibody; (ii) allow intracellular delivery of the conjugate or drug moiety; (iii) remain stable and intact, i.e.
- Stability of the ADC may be measured by standard analytical techniques such as mass spectroscopy, HPLC, and the separation/analysis technique LC/MS. Covalent attachment of the antibody and the drug moiety requires the linker to have two reactive functional groups, i.e. bivalency in a reactive sense.
- Bivalent linker reagents which are useful to attach two or more functional or biologically active moieties, such as peptides, nucleic acids, drugs, toxins, antibodies, haptens, and reporter groups are known, and methods have been described their resulting conjugates (Hermanson, G. T. (1996) Bioconjugate Techniques; Academic Press: New York, p.234-242).
- Suitable cleavable linkers include those that may be cleaved, for instance, by enzymatic hydrolysis, photolysis, hydrolysis under acidic conditions, hydrolysis under basic conditions, oxidation, disulfide reduction, nucleophilic cleavage, or organometallic cleavage (see, for example, Leriche et al., Bioorg. Med.
- Suitable cleavable linkers may include, for example, chemical moieties such as a hydrazine, a disulfide, a thioether or a dipeptide.
- Linkers hydrolyzable under acidic conditions include, for example, hydrazones, semicarbazones, thiosemicarbazones, cis-aconitic amides, orthoesters, acetals, ketals, or the like. (See, e.g., U.S. Pat.
- linkers suitable for covalent conjugation are relatively stable under neutral pH conditions, such as those in the blood, but are unstable at below pH 5.5 or 5.0, the approximate pH of the lysosome.
- Linkers cleavable under reducing conditions include, for example, a disulfide.
- disulfide linkers are known in the art, including, for example, those that can be formed using SATA (N-succinimidyl-S-acetylthioacetate), SPDP (N-succinimidyl-3-(2- pyridyldithio)propionate), SPDB (N-succinimidyl-3-(2-pyridyldithio)butyrate) and SMPT (N- succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyl-dithio)toluene), SPDB and SMPT (See, e.g., Thorpe et al., 1987, Cancer Res.47:5924-5931; Wawrzynczak et al., In Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (C.
- linkers suitable for covalent conjugation include those capable of releasing a cytotoxin by a 1,6-elimination process (a "self-immolative" group), such as p-aminobenzyl alcohol (PABC), p-aminobenzyl (PAB), 6- maleimidohexanoic acid, pH-sensitive carbonates, and other reagents described in Jain et al., Pharm.
- PABC p-aminobenzyl alcohol
- PAB p-aminobenzyl
- 6- maleimidohexanoic acid pH-sensitive carbonates
- the linker includes a self-immolative group such as the afore- mentioned PAB or PABC (para-aminobenzyloxycarbonyl), which are disclosed in, for example, Carl et al., J. Med. Chem. (1981) 24:479-480; Chakravarty et al (1983) J. Med.
- PAB para-aminobenzyloxycarbonyl
- Linkers susceptible to enzymatic hydrolysis can be, e.g., a peptide-containing linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease.
- the peptidyl linker is at least two amino acids long or at least three amino acids long.
- Exemplary amino acid linkers include a dipeptide, a tripeptide, a tetrapeptide or a pentapeptide.
- suitable peptides include those containing amino acids such as Valine, Alanine, Citrulline (Cit), Phenylalanine, Lysine, Leucine, and Glycine.
- Amino acid residues which comprise an amino acid linker component include those occurring naturally, as well as minor amino acids and non- naturally occurring amino acid analogs, such as citrulline.
- Exemplary dipeptides include valine- citrulline (vc or val-cit) and alanine-phenylalanine (af or ala-phe).
- Exemplary tripeptides include glycine-valine-citrulline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly).
- the linker includes a dipeptide such as Val-Cit, Ala-Val, or Phe-Lys, Val-Lys, Ala- Lys, Phe-Cit, Leu-Cit, Ile-Cit, Phe-Arg, or Trp-Cit.
- Linkers containing dipeptides such as Val-Cit or Phe-Lys are disclosed in, for example, U.S. Pat. No.6,214,345, the disclosure of which is incorporated herein by reference in its entirety as it pertains to linkers suitable for covalent conjugation.
- the linker includes a dipeptide selected from Val-Ala and Val-Cit.
- a dipeptide is used in combination with a self-immolative linker.
- Linkers suitable for use herein further may include one or more groups selected from C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene, C 2 -C 6 alkenylene, C 2 -C 6 heteroalkenylene, C 2 -C 6 alkynylene, C 2 -C 6 heteroalkynylene, C 3 -C 6 cycloalkylene, heterocycloalkylene, arylene, heteroarylene, and combinations thereof, each of which may be optionally substituted.
- each C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 heteroalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 heteroalkynyl, C 3 -C 6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may be optionally substituted with from 1 to 5 substituents independently selected for each occasion from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, halogen,
- each C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 heteroalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 heteroalkynyl, C 3 -C 6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may optionally be interrupted by one or more heteroatoms selected from O, S and N.
- each C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 heteroalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 heteroalkynyl, C3-C 6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may optionally be interrupted by one or more heteroatoms selected from O, S and N and may be optionally substituted with from 1 to 5 substituents independently selected for each occasion from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl,
- Suitable linkers may contain groups having solubility enhancing properties.
- Linkers including the (CH 2 CH 2 O)p unit polyethylene glycol, PEG), for example, can enhance solubility, as can alkyl chains substituted with amino, sulfonic acid, phosphonic acid or phosphoric acid residues.
- Linkers including such moieties are disclosed in, for example, U.S. Patent Nos. 8,236,319 and 9,504,756, the disclosure of each of which is incorporated herein by reference in its entirety as it pertains to linkers suitable for covalent conjugation.
- Such solubility enhancing groups include, for example, acyl and carbamoyl sulfamide groups, having the structure: wherein a is 0 or 1; and R 10 is selected from the group consisting of hydrogen, C 1 -C 24 alkyl groups, C 3 -C 24 cycloalkyl groups, C 1 -C 24 (hetero)aryl groups, C 1 -C 24 alkyl(hetero)aryl groups and C 1 -C 24 (hetero)arylalkyl groups, the C 1 -C 24 alkyl groups, C 3 -C 24 cycloalkyl groups, C 2 -C 24 (hetero)aryl groups, C 3 -C 24 alkyl(hetero)aryl groups and C 3 -C 24 (hetero)arylalkyl groups, each of which may be optionally substituted and/or optionally interrupted by one or more heteroatoms selected from O, S and NR 11 R 12 , wherein R 11 and R 12 are independently selected from
- linkers containing such groups are described, for example, in U.S. Patent No.9,636,421 and U.S. Patent Application Publication No.2017/0298145, the disclosures of which are incorporated herein by reference in their entirety as they pertain to linkers suitable for covalent conjugation to cytotoxins and antibodies or antigen-binding fragments thereof.
- the linker comprises a ((CH 2 )mO) n(CH 2 )m– group where n and m are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and a heteroaryl group, wherein the heteroaryl group is a triazole.
- the ((CH 2 )mO) n(CH 2 )m– group and triazole together comprise , where n is from 1 to 10, and the wavy lines indicate attachment points to additional linker components, the chemical moiety Z, or the amatoxin.
- linkers that may be used in the methods and compositions described herein are described in US 2019/0144504, which is incorporated by reference herein.
- the linker includes a p-aminobenzyl group (PAB).
- PAB p-aminobenzyl group
- the p-aminobenzyl group is disposed between the cytotoxic drug and a protease cleavage site in the linker.
- the p-aminobenzyl group is part of a p- aminobenzyloxycarbonyl unit.
- the p-aminobenzyl group is part of a p- aminobenzylamido unit.
- the linker comprises PAB, Val-Cit-PAB, Val-Ala- PAB, Val-Lys(Ac)-PAB, Phe-Lys-PAB, Phe-Lys(Ac)-PAB, D-Val-Leu-Lys, Gly-Gly-Arg, Ala-Ala- Asn-PAB, or Ala-PAB.
- the linker comprises a combination of one or more of a peptide, oligosaccharide, -(CH 2 )n-, -(CH 2 CH 2 O)n-, PAB, Val-Cit-PAB, Val-Ala-PAB, Val-Lys(Ac)-PAB, Phe-Lys-PAB, Phe-Lys(Ac)-PAB, D-Val-Leu-Lys, Gly-Gly-Arg, Ala-Ala-Asn-PAB, or Ala-PAB.
- the linker comprises PAB-Ala-Val-propionyl, represented by the structure wherein the wavy lines indicate attachment points to the cytotoxin and the reactive moiety Z′.
- the linker comprises PAB-Cit-Val-propionyl, represented by the structure
- the linker of the ADC is maleimidocaproyl-Val-Ala-para- aminobenzyl (mc-Val-Ala-PAB). In certain embodiments, the linker of the ADC is maleimidocaproyl-Val-Cit-para- aminobenzyl (mc-vc-PAB). In some embodiments, the linker comprises .
- Linkers that can be used to conjugate an antibody, or antigen-binding fragment thereof, to a cytotoxic agent include those that are covalently bound to the cytotoxic agent on one end of the linker and, on the other end of the linker, contain a chemical moiety formed from a coupling reaction between a reactive substituent present on the linker and a reactive substituent present within the antibody, or antigen-binding fragment thereof, that binds CD117 (such as GNNK+ CD117).
- Reactive substituents that may be present within an antibody, or antigen-binding fragment thereof, that binds CD117 include, without limitation, hydroxyl moieties of serine, threonine, and tyrosine residues; amino moieties of lysine residues; carboxyl moieties of aspartic acid and glutamic acid residues; and thiol moieties of cysteine residues, as well as propargyl, azido, haloaryl (e.g., fluoroaryl), haloheteroaryl (e.g., fluoroheteroaryl), haloalkyl, and haloheteroalkyl moieties of non-naturally occurring amino acids.
- haloaryl e.g., fluoroaryl
- haloheteroaryl e.g., fluoroheteroaryl
- haloalkyl e.g., fluoroheteroaryl
- linkers useful for the synthesis of drug-antibody conjugates conjugates include those that contain electrophiles, such as Michael acceptors (e.g., maleimides), activated esters, electron-deficient carbonyl compounds, and aldehydes, among others, suitable for reaction with nucleophilic substituents present within antibodies or antigen-binding fragments, such as amine and thiol moieties.
- electrophiles such as Michael acceptors (e.g., maleimides), activated esters, electron-deficient carbonyl compounds, and aldehydes, among others, suitable for reaction with nucleophilic substituents present within antibodies or antigen-binding fragments, such as amine and thiol moieties.
- linkers suitable for the synthesis of drug- antibody conjugates include, without limitation, succinimidyl 4-(N-maleimidomethyl)- cyclohexane-L-carboxylate (SMCC), N- succinimidyl iodoacetate (SIA), sulfo-SMCC, m- maleimidobenzoyl-N-hydroxysuccinimidyl ester (MBS), sulfo-MBS, and succinimidyl iodoacetate, among others described, for instance, Liu et al., 18:690-697, 1979, the disclosure of which is incorporated herein by reference as it pertains to linkers for chemical conjugation.
- SMCC succinimidyl 4-(N-maleimidomethyl)- cyclohexane-L-carboxylate
- SIA N- succinimidyl iodoacetate
- MBS m- maleimidobenzoyl-N-hydroxysuccinimidy
- Additional linkers include the non-cleavable maleimidocaproyl linkers, which are particularly useful for the conjugation of microtubule-disrupting agents such as auristatins, are described by Doronina et al., Bioconjugate Chem.17:14-24, 2006, the disclosure of which is incorporated herein by reference as it pertains to linkers for chemical conjugation. It will be recognized by one of skill in the art that any one or more of the chemical groups, moieties and features disclosed herein may be combined in multiple ways to form linkers useful for conjugation of the antibodies and cytotoxins as disclosed herein. Further linkers useful in conjunction with the compositions and methods described herein, are described, for example, in U.S.
- Linkers useful in conjunction with the antibody-drug described herein include, without limitation, linkers containing chemical moieties formed by coupling reactions as depicted in Table 2, below. Curved lines designate points of attachment to the antibody, or antigen-binding fragment, and the cytotoxic molecule, respectively. Table 2. Exemplary chemical moieties Z formed by coupling reactions in the formation of antibody-drug
- antibody-drug conjugates useful in conjunction with the methods described herein may be formed by the reaction of an antibody, or antigen-binding fragment thereof, with a linker or cytotoxin-linker conjugate, as described herein, the linker or cytotoxin- linker conjugate including a reactive substituent Z', suitable for reaction with a reactive substituent on the antibody, or antigen-binding fragment thereof, to form the chemical moiety Z.
- R 13 is independently selected for each occasion from H and C 1 -C 6 alkyl
- R 16 is independently selected for each occasion from H, Ci-Ce alkyl, F, Cl, and -OH;
- R 17 is independently selected for each occasion from H, C 1 -C 6 alkyl, F, Cl, -NH 2 , -OCH 3 , -OCH 2 CH 3 , -N(CH 3 ) 2 , -CN, -NO 2 and-OH;
- suitably reactive substituents on the linker and antibody or antigen-binding fragment thereof include a nucleophile/electrophile pair (e.g., a thiol/haloalkyl pair, an amine/carbonyl pair, or a thiol/ ⁇ , ⁇ -unsaturated carbonyl pair, and the like), a diene/dienophile pair (e.g., an azide/alkyne pair, or a diene/ ⁇ , ⁇ -unsaturated carbonyl pair, among others), and the like.
- a nucleophile/electrophile pair e.g., a thiol/haloalkyl pair, an amine/carbonyl pair, or a thiol/ ⁇ , ⁇ -unsaturated carbonyl pair, and the like
- a diene/dienophile pair e.g., an azide/alkyne pair, or a diene/ ⁇ , ⁇ -
- Coupling reactions between the reactive substitutents to form the chemical moiety Z include, without limitation, thiol alkylation, hydroxyl alkylation, amine alkylation, amine or hydroxylamine condensation, hydrazine formation, amidation, esterification, disulfide formation, cycloaddition (e.g., [4+2] Diels-Alder cycloaddition, [3+2] Huisgen cycloaddition, among others), nucleophilic aromatic substitution, electrophilic aromatic substitution, and other reactive modalities known in the art or described herein.
- the linker contains an electrophilic functional group for reaction with a nucleophilic functional group on the antibody, or antigen- binding fragment thereof.
- Reactive substituents that may be present within an antibody, or antigen-binding fragment thereof, as disclosed herein include, without limitation, nucleophilic groups such as (i) N-terminal amine groups, (ii) side chain amine groups, e.g. lysine, (iii) side chain thiol groups, e.g. cysteine, and (iv) sugar hydroxyl or amino groups where the antibody is glycosylated.
- nucleophilic groups such as (i) N-terminal amine groups, (ii) side chain amine groups, e.g. lysine, (iii) side chain thiol groups, e.g. cysteine, and (iv) sugar hydroxyl or amino groups where the antibody is glycosylated.
- Reactive substituents that may be present within an antibody, or antigen-binding fragment thereof, as disclosed herein include, without limitation, hydroxyl moieties of serine, threonine, and tyrosine residues; amino moieties of lysine residues; carboxyl moieties of aspartic acid and glutamic acid residues; and thiol moieties of cysteine residues, as well as propargyl, azido, haloaryl (e.g., fluoroaryl), haloheteroaryl (e.g., fluoroheteroaryl), haloalkyl, and haloheteroalkyl moieties of non-naturally occurring amino acids.
- haloaryl e.g., fluoroaryl
- haloheteroaryl e.g., fluoroheteroaryl
- haloalkyl e.g., fluoroheteroaryl
- the reactive substituents present within an antibody, or antigen-binding fragment thereof as disclosed herein include, are amine or thiol moieties.
- Certain antibodies have reducible interchain disulfides, i.e. cysteine bridges.
- Antibodies may be made reactive for conjugation with linker reagents by treatment with a reducing agent such as DTT (dithiothreitol).
- DTT dithiothreitol
- Each cysteine bridge will thus form, theoretically, two reactive thiol nucleophiles. Additional nucleophilic groups can be introduced into antibodies through the reaction of lysines with 2-iminothiolane (Traut's reagent) resulting in conversion of an amine into a thiol.
- Reactive thiol groups may be introduced into the antibody (or fragment thereof) by introducing one, two, three, four, or more cysteine residues (e.g., preparing mutant antibodies comprising one or more non-native cysteine amino acid residues).
- U.S. Pat. No.7,521,541 teaches engineering antibodies by introduction of reactive cysteine amino acids.
- the reactive moiety Z' attached to the linker is a nucleophilic group which is reactive with an electrophilic group present on an antibody.
- Useful electrophilic groups on an antibody include, but are not limited to, aldehyde and ketone carbonyl groups.
- the heteroatom of a nucleophilic group can react with an electrophilic group on an antibody and form a covalent bond to the antibody.
- Useful nucleophilic groups include, but are not limited to, hydrazide, oxime, amino, hydroxyl, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide.
- Z is the product of a reaction between reactive nucleophilic substituents present within the antibodies, or antigen-binding fragments thereof, such as amine and thiol moieties, and a reactive electrophilic substituent Z'.
- Z' may be a Michael acceptor (e.g., maleimide), activated ester, electron-deficient carbonyl compound, or an aldehyde, among others.
- Michael acceptor e.g., maleimide
- activated ester e.g., activated ester
- electron-deficient carbonyl compound e.g., carbonyl compound
- aldehyde e.g., aldehyde
- linkers suitable for the synthesis of ADCs of the disclosure include, without limitation, reactive substituents Z′ such as maleimide or haloalkyl groups. These may be attached to the linker by reagents such as succinimidyl 4-(N-maleimidomethyl)-cyclohexane-L- carboxylate (SMCC), N- succinimidyl iodoacetate (SIA), sulfo-SMCC, m-maleimidobenzoyl-N- hydroxysuccinimidyl ester (MBS), sulfo-MBS, and succinimidyl iodoacetate, among others described, in for instance, Liu et al., 18:690-697, 1979, the disclosure of which is incorporated herein by reference as it pertains to linkers for chemical conjugation.
- reagents such as succinimidyl 4-(N-maleimidomethyl)-cyclohexane-L- carboxylate (SMCC), N-
- the reactive substituent Z′ attached to linker L is a maleimide, azide, or alkyne.
- a maleimide-containing linker is the non-cleavable maleimidocaproyl-based linker.
- the reactive substituent is an N-maleimidyl group, halogenated N-alkylamido group, sulfonyloxy N-alkylamido group, carbonate group, sulfonyl halide group, thiol group or derivative thereof, alkynyl group comprising an internal carbon-carbon triple bond, (het-ero)cycloalkynyl group, bicyclo[6.1.0]non-4-yn-9-yl group, alkenyl group comprising an internal carbon-carbon double bond, cycloalkenyl group, tetrazinyl group, azido group, phosphine group, nitrile oxide group, nitrone group, nitrile imine group, diazo group, ketone group, (O-alkyl)hydroxylamino group, hydrazine group, halogenated N-maleimidyl group, 1,1-bis (sulfonylmethyl)methylcarbonyl group or elimination
- the reactive substituent comprises a cycloalkene group, a cycloalkyne group, or an optionally substituted (hetero)cycloalkynyl group.
- the anti-CD117 ADC comprises an anti-CD117 antibody conjugated to an amatoxin of formula I as disclosed herein, via a linker and a chemical moiety Z.
- the linker includes a hydrazine, a disulfide, a thioether or a dipeptide.
- the linker includes a dipeptide selected from Val-Ala and Val-Cit.
- the linker includes a para-aminobenzyl group (PAB).
- an amatoxin as disclosed herein is conjugated to a linker- reactive moiety -L-Z′ having the following formula: , where the wavy line indicates the point of attachment to a substituent on the cytotoxin (e.g., an amatoxin).
- This linker-reactive substituent group L-Z' may alternatively be referred to as N-beta- maleimidopropionyl-Val-Ala-para-aminobenzyl (BMP-Val-Ala-PAB).
- an amatoxin as disclosed herein is conjugated to a linker- reactive moiety -L-Z′ having the following formula: , where the wavy line indicates the point of attachment to a substituent on the cytotoxin (e.g., an amatoxin).
- This linker-reactive substituent group L-Z' may alternatively be referred to as N-beta- maleimidopropyl-Val-Cit-para-aminobenzyl (BMP-Val-Cit-PAB).
- the linker-reactive substituent group structure L-Z' prior to conjugation with the antibody or antigen binding fragment thereof, is:
- the linker L and the chemical moiety Z, taken together as L-Z is where S is a sulfur atom which represents the reactive substituent present within an antibody, or antigen-binding fragment thereof, such as an anti-CD117 antibody (e.g., from the - SH group of a cysteine residue).
- S is a sulfur atom which represents the reactive substituent present within an antibody, or antigen-binding fragment thereof, such as an anti-CD117 antibody (e.g., from the - SH group of a cysteine residue).
- the wavy line at the linker terminus indicates the point of attachment to the amatoxin.
- the linker L and the chemical moiety Z after conjugation to the antibody, taken together as L-Z-Ab, has the structure: where S is a sulfur atom which represents the reactive substituent present within an antibody, or antigen-binding fragment thereof, such as an anti-CD-117 antibody.
- S is a sulfur atom which represents the reactive substituent present within an antibody, or antigen-binding fragment thereof, such as an anti-CD-117 antibody.
- the wavy line at the linker terminus indicates the point of attachment to the amatoxin.
- the linker- reactive substituent group structure prior to conjugation with the antibody or antigen binding fragment thereof, includes a maleimide as the group Z'.
- the foregoing linker moieties and amatoxin-linker conjugates, among others useful in conjunction with the compositions and methods described herein, are described, for example, in U.S.
- an ant-CD117 antibody or antigen binding fragment thereof is conjugated to one or more cytotoxic drug moieties (D), e.g. about 1 to about 20 drug moieties per antibody, through a linker L and a chemical moiety Z as disclosed herein.
- D cytotoxic drug moieties
- the ADCs of the present disclosure may be prepared by several routes, employing organic chemistry reactions, conditions, and reagents known to those skilled in the art, including: (1) reaction of a reactive substituent of an antibody or antigen binding fragment thereof with a bivalent linker reagent to form Ab-Z-L as described herein above, followed by reaction with a drug moiety D; or (2) reaction of a reactive substituent of a drug moiety with a bivalent linker reagent to form D-L-Z, followed by reaction with a reactive substituent of an antibody or antigen binding fragment thereof as described herein above to form an ADC of formula D-L-Z-Ab, such as Am-Z-L-Ab. Additional methods for preparing ADC are described herein.
- the antibody or antigen binding fragment thereof has one or more lysine residues that can be chemically modified to introduce one or more sulfhydryl groups.
- the ADC is then formed by conjugation through the sulfhydryl group's sulfur atom as described herein above.
- the reagents that can be used to modify lysine include, but are not limited to, N- succinimidyl S-acetylthioacetate (SATA) and 2-Iminothiolane hydrochloride (Traut's Reagent).
- the antibody or antigen binding fragment thereof can have one or more carbohydrate groups that can be chemically modified to have one or more sulfhydryl groups.
- the ADC is then formed by conjugation through the sulfhydryl group's sulfur atom as described herein above.
- the antibody can have one or more carbohydrate groups that can be oxidized to provide an aldehyde (-CHO) group (see, for e.g., Laguzza, et al., J. Med. Chem. 1989, 32(3), 548-55).
- the ADC is then formed by conjugation through the corresponding aldehyde as described herein above.
- Other protocols for the modification of proteins for the attachment or association of cytotoxins are described in Coligan et al., Current Protocols in Protein Science, vol.2, John Wiley & Sons (2002), incorporated herein by reference.
- linker-drug moieties to cell-targeted proteins such as antibodies, immunoglobulins or fragments thereof are found, for example, in U.S. Pat. No. 5,208,020; U.S. Pat. No.6,441,163; WO2005037992; WO2005081711; and WO2006/034488, all of which are hereby expressly incorporated by reference in their entirety.
- linker moieties and amatoxin-linker conjugates are described, for example, in U.S. Patent Application Publication No.2015/0218220 and Patent Application Publication No.
- the MGTA-117 antibody refers to Ab85 with an Fc region comprising D265C, L234A, L235A, and H435A mutations (i.e., the Ab85 comprising a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 9 and a light chain having an amino acid sequence as set forth in SEQ ID NO: 10 and conjugated to an amatoxin).
- Example 1 Use of Anti-CD117 ADC for Conditioning for HSC Transplantation This example provides details of a study examining dose and time relationship between dosing of MGTA-117 and the resulting depletion of bone marrow stem cells and peripheral reticulocytes utilizing a non-human primate (NHP) model.
- NEP non-human primate
- Hematopoietic stem cell transplant is a highly effective and potentially curative treatment for malignant and non-malignant blood disorders.
- current conditioning regimens which are non-selective and used with toxic multi-dosing regimens limit the use of HSCT due to regimen-related mortality and morbidities including organ toxicity, infertility, and secondary malignancies.
- ADC targeted antibody-drug conjugate
- MGTA-117 Upon binding to CD117, MGTA-117 is rapidly internalized and, following the lysosomal degradation and subsequent release of the amanitin payload intracellularly, inhibits RNA polymerase 2 leading to apoptosis of quiescent and cycling cells (data not shown).
- the antibody component of the ADC was engineered for rapid clearance and is an antagonist of Stem Cell Factor (SCF), the natural ligand for CD117, providing a dual mechanism of target cell depletion.
- SCF Stem Cell Factor
- MGTA-117 In NHPs, a single administration of MGTA-117 resulted in significant depletion of stem and progenitor cells in the bone marrow and peripheral blood reticulocytes reflecting the depletion of erythroid precursors.
- the data presented are pooled across several individual studies with MGTA-117 in cynomolgus NHPs.
- MGTA-117 was dosed at 0.05 to 3 mg/kg via intravenous infusion over 60 minutes in NHPs to determine the time course of pharmacokinetic (PK) and pharmacodynamic (PD) conditioning responses within stem cell and blood populations.
- Tissue sample collection i.e., peripheral blood or bone marrow aspirate
- Standard hematology measurements were also collected to evaluate non-targeted responses to MGTA-117 administration.
- Flow cytometry analysis was performed on peripheral blood and bone marrow aspirate samples.
- stem cells counts single cells in a heterogeneous mixture were detected, counted, sorted, and profiled via single-file cell passage through flow cytometry.
- Cell composition was assessed using fluorescently conjugated antibodies against specific cell surface markers. Fluorescently conjugated antibodies are excited by a laser to emit light at specific wavelengths. Fluorescent emission is measured by an electronic detection apparatus as light scatter and fluorescence intensity. Specific cell populations within the heterogenous mixture were identified and quantified based on their emission profile.
- reticulocytes counts For estimation of reticulocytes counts, standard hematology samples were collected and analyzed at the in-life testing facilities. For PK analysis, an enzyme-linked immunosorbent assay (ELISA)-based assay was utilized for the estimation of ADC and therapeutic antibodies within each individual study. PK data presented reflect the mean ( ⁇ SD) ADC concentrations collected within each animal receiving MGTA-117 after pooling the data at each relevant dose. The lower limit of quantification for MGTA-117 was consistent across each study. Intravenous administration of MGTA-117 resulted in dose-dependent increases in exposures, with rapid rates of clearance at all dose levels.
- ELISA enzyme-linked immunosorbent assay
- Nonlinear rates of clearance were apparent at the higher doses of MGTA-117, consistent with the expected target-mediated drug distribution profile, where nonlinear clearance is attributed to saturation of CD117 binding and internalization of the ADC. Even at the highest doses tested, MGTA-117 was cleared quickly and was below the limit of quantification in blood 10 days post dose (Fig.1). Within NHPs, greater than 90% depletion of CD34+/CD90+/45RA- stem cells within bone marrow were observed at doses of 0.3 mg/kg and higher (Fig.3A-B).
- MGTA-117 While the onset of reticulocyte depletion is similar to stem cell populations, the relative recovery appears to correlate directly with the clearance of MGTA-117 below active concentrations. Blood neutrophils and platelets were largely unaffected by any dose of MGTA-117 on day 7 (data not shown), confirming the targeted effects on CD117+ expressing cell populations. MGTA-117 was well-behaved with consistent PK-PD across a wide range of doses within NHPs. MGTA-117 demonstrated rapid clearance from blood. The observed dose- dependent changes in clearance are consistent with saturation of receptor binding and internalization. At doses of 0.3 mg/kg and higher, the observed PD responses confirm targeted depletion of CD117-expressing populations, with lasting stem cell responses beyond the actual clearance of ADC.
- CD117+ CD117 positive cells from human patients with adult acute myeloid leukemia (AML) and myelodysplasia-excess blasts (MDS-EB).
- AML adult acute myeloid leukemia
- MDS-EB myelodysplasia-excess blasts
- the study also will evaluate anti-drug antibodies (ADA).
- the study consists of escalating single-dose cohorts using a standard 3+3 design.
- MGTA-117 is an anti-CD117 ADC comprising antibody Ab85 (human IgG1) and an amanitin with a non-cleavable linker.
- Subjects were treated with a single dose of MGTA-117 prepared and administered by IV infusion over a 1-hour period.
- the primary objectives of the study included (i) characterization of the safety and tolerability of MGTA-117 in participants; (ii) characterization of the PK profile of MGTA-117 in relapsed/refractory AML (R/R AML) and MDS-EB participants; and (iii) establishment of a minimum safe and biologically effective dose of MGTA-117 in participants.
- the flowing primary outcomes were chosen for assessment: 1.
- Pharmacokinetics profile of MGTA-117 [ Time Frame: 21 days ]; Investigate area under the curve (AUC) 5.
- Pharmacokinetics profile of MGTA-117 [ Time Frame: 21 days ] Investigate the half-life (t1/2) 8. Pharmacokinetics profile of MGTA-117 [ Time Frame: 21 days ] Investigate the plasma concentration 9.
- To establish a minimum safe and biologically effective dose [ Time Frame: 7 days ] Assess the CD117 receptor occupancy in circulating leukemic blasts 10.
- To establish a minimum safe and biologically effective dose [ Time Frame: 21 days ] Objectives of the study include (i) assessing the PD of MGTA-117 in participants; (ii) characterizing the immunogenicity of MGTA-117 in participants; and (iii) assessing the preliminary anti-leukemic activity of MGTA-117 and changes in HSCs.
- Participant must have a World Health Organization (WHO)-defined diagnosis of R/R AML and meet one of the following criteria: - The participant has experienced primary AML induction failure or R/R AML OR - The participant has a WHO-defined diagnosis of MDS-EB and has failed/is refractory to HMA OR - Presence of MRD in morphologic CR 2. CD117+ based on IHC or flow cytometry 3. Participant must have an identified HSC donor (related donor or unrelated donor), haplo- identical transplant donor, or umbilical blood donor. 4. Participant's Eastern Cooperative Oncology Group (ECOG) performance status must be ⁇ 2. 5.
- WHO World Health Organization
- Participant has a history of serious allergic reactions, which in the opinion of the Investigator may pose an increased risk of serious infusion reactions. 12. Participant has had any systemic antileukemia treatment within 14 days except hydroxyurea, which is permitted until 24 hours prior to MGTA-117 dosing. 13. Participant has received prior anti-CD117 antibody treatment. 14. Participant has received gemtuzumab ozogamicin (Mylotarg) within the last 3 months prior to dosing. 15. Participant has received recent monoclonal antibody as anti-leukemic therapy within the last 30 days or 5 half-lives, whichever is longer. 16. Participant has received recent vaccination within the last 14 days prior to dosing. 17.
- Example 3 Results from the First-in-Human Clinical Trial for MGTA-117 (Anti-CD117 ADC) This example provides initial results for cohorts 1-3 from the clinical trial described in Example 2. Baseline demographics are provided in Table 5. The R/R AML study population had a poor prognosis with a high burden of disease despite multiple previous lines of therapy.
- MGTA-117 is well tolerated at low doses.
- Treatment-emergent AEs (TEAE) were generally consistent with the underlying disease and associated complications. There were no unexpected AEs, TEAEs, treatment-related deaths, treatment-related infusion reactions, or dose-limiting toxicities observed. The observed treatment-related AEs were expected, transient, low-grade, and resolved without any intervention. There were no treatment-related infusion reactions observed. Importantly, no MGTA-117-related TEAEs led to study discontinuation.
- MGTA-117 concentrations were measured at 0, 0.25, 2, 4, 8, 24, 36, and 48 hours following the infusion. Maximum concentrations of MGTA-117 were reached within 1 hour of the infusion. MGTA-117 was rapidly cleared, with a T1/2 of 10 hours or less. No measurable MGTA-117 was detected at 48 hours following the infusion across all three doses tested (Fig.4). Further, free amanitin-containing payload was undetectable in blood across all participants. MGTA-117 rapidly bound CD117+ blast cells in blood, as measured by a receptor occupancy assay.
- the percent of receptor occupancy (RO) in blast cells was measured at 0, 0.25, 2, 4, 8, 24, and 48 hours following the infusion of MGTA-117 as described in Fig.5. Binding of CD117+ cells was observed in all participants at 15-minute initial measurement after dosing. RO decline was observed in all dosed participants indicating internalization of MGTA- 117. Higher receptor occupancy was observed in Cohorts 2 and 3 relative to Cohort 1. Longer duration of receptor occupancy was observed in Cohorts 2 and 3 relative to Cohort 1. The ability for MGTA-117 to deplete CD117+ blast cells was measured in blood samples. This depletion is described in Fig.6 for Cohorts 1-3. CD117 + blast cell depletion was observed in the blood in Cohorts 2 and 3.
- MGTA-117 depleted blasts in blood AND bone marrow in 3 participants (#11, 13, 14) in Cohort 3.
- Two relapsed/refractory participants achieved complete remission (CR), specifically one participant with AML participant (Cohort 1), one participant with MDS (Cohort 3). Both participants had similar clinical morphology to transplant-eligible patients at baseline due to low blast counts in the blood and bone marrow.
- anti-leukemic Based on the results from early-stage cohorts, MGTA-117 has demonstrated potential as a safe, well-tolerated, and efficacious therapeutic for depleting CD117+ cells in patients prior to HSCT (i.e., as a conditioning agent).
- a first case study is presented for participant 2 in cohort 1.
- MRD minimal residual disease
- MGTA-117 has further demonstrated potential as a conditioning regimen for a patient diagnosed with MDS prior to HSCT.
- a second case study is presented for participant 14 in cohort 3. Said participant, a 73-year-old female, was initially diagnosed with ASXL1, BCOR, U2AF1 mutation positive, treatment refractory MDS. She presented with 17% bone marrow blasts at the time of diagnosis. She received decitabine treatment for 1 year. At the time of screening for the study, she presented with 10% bone marrow blasts.7 days after treatment with MGTA-117 at 0.08 mg/kg, she entered complete remission and was MRD positive with 3% bone marrow blasts, rendering her transplant eligible.
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Abstract
The invention relates to uses of an anti-CD117 antibody drug conjugate (ADC) comprising an anti-CD117 antibody conjugated to an amatoxin via a linker, for targeted conditioning a human patient in need thereof for hematopoietic stem cell (HSC) transplantation. Also provided is a method for depleting CD117+ cells, e.g., endogenous HSCs, in a human patient in need thereof.
Description
USE OF ANTI-CD117 ANTIBODY DRUG CONJUGATE (ADC) Cross-Reference To Related Applications This application claims the benefit of U.S. Provisional Application No.63/386,891, filed December 9, 2022, and U.S. Provisional Application No.63/386,919, filed December 11, 2022, and U.S. Provisional Application No.63/479,535, filed January 11, 2023, the content of each of which is herein incorporated by reference in their entirety. Sequence Listing Statement The contents of the electronic sequence listing titled CRISP_42003_601_SQL.xml (Size: 10,549 bytes; and Date of Creation: September 27, 2023) is herein incorporated by reference in its entirety. Background CD117 (also referred to as c-kit or Stem Cell Factor Receptor (SCRF)) is a single transmembrane, receptor tyrosine kinase that binds the ligand Stem Cell Factor (SCF). SCF induces homodimerization of CD117 which activates its tyrosine kinase activity and signals through both the P13-AKT and MAPK pathways (Kindblom et al., Am J. Path.1998 152(5):1259). CD117 was initially discovered as an oncogene and has been studied in the field of oncology (see, for example, Stankov et al. (2014) Curr Pharm Des.20(17):2849-80). CD117 is highly expressed on hematopoietic stem cells (HSCs). Hematopoietic stem cell transplant is a highly effective and potentially curative treatment for malignant and non-malignant blood disorders. Current conditioning regimens which are non- selective and used with toxic multi-dosing regimens limit the use of HSCT due to regimen- related mortality and morbidities including organ toxicity, infertility, and secondary malignancies. There remains, however, a need for anti-CD117 based therapy that is effective for conditioning responses, including within stem cell and reticulocytes populations. Summary Described herein are methods for targeted conditioning a human patient for a hematopoietic stem cell transplantation, as well as gene therapy. Also described are methods for depleting CD117+ cells in a human subject in need thereof.
In one embodiment, the present invention provides a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of from about 0.02 to about 3.0 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, and wherein the antibody comprises a heavy chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 3, 4, and 5, respectively, and comprises a light chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 6, 7, and 8, respectively, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In another embodiment, the present invention provides a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of from about 0.02 to about 3.0 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, and wherein the anti-CD117 antibody comprises a heavy chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 3, 4, and 5, respectively, and comprises a light chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 6, 7, and 8, respectively, such that the human patient is conditioned for an HSC transplant. In another embodiment, the present invention provides an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, and wherein the antibody comprises a heavy chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 3, 4, and 5, respectively, and comprises a light chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 6, 7, and 8, respectively, for use in depleting a population of CD117+ cells in a human patient in need thereof, wherein the ADC is administered to the patient in a dosage of from about 0.02 to about 3.0 mg/kg. In another embodiment, the present invention provides an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, and wherein the antibody comprises a heavy chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 3, 4, and 5, respectively, and comprises a light chain variable region comprising a CDR1,
CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 6, 7, and 8, respectively, for use in conditioning a human patient for an hematopoietic stem cell (HSC) transplant, wherein the ADC is administered to the patient in a dosage of from about 0.02 to about 3.0 mg/kg. In some preferred embodiments, the dosage is be selected from the group consisting of about 0.02, 0.04, 0.076, 0.08.0.127, 0.13, 0.15, 0.19, 0.247, 0.30, 0.309, 0.386, 0.483, 0.603, 0.754, 0.942, 1.0, and 3.0 mg/kg. In some embodiments, the dosage is about 0.02 mg/kg. In some embodiments, the dosage is about 0.04 mg/kg. In some embodiments, the dosage is about 0.076 mg/kg. In some embodiments, the dosage is about 0.08 mg/kg. In some embodiments, the dosage is about 0.127 mg/kg. In some embodiments, the dosage is about 0.13 mg/kg. In some embodiments, the dosage is about 0.15 mg/kg. In some embodiments, the dosage is about 0.19 mg/kg. In some embodiments, the dosage is about 0.247 mg/kg. In some embodiments, the dosage is about 0.30 mg/kg. In some embodiments, the dosage is about 0.309 mg/kg. In some embodiments, the dosage is about 0.386 mg/kg. In some embodiments, the dosage is about 0.483 mg/kg. In some embodiments, the dosage is about 0.603 mg/kg. In some embodiments, the dosage is about 0.754 mg/kg. In some embodiments, the dosage is about 0.942 mg/kg. In some embodiments, the dosage is about 1.0 mg/kg. In some embodiments, the dosage is about 2.0 mg/kg. In some embodiments, the dosage is about 3.0 mg/kg. In some embodiments, the dosage is 0.02 mg/kg. In some embodiments, the dosage is 0.04 mg/kg. In some embodiments, the dosage is 0.076 mg/kg. In some embodiments, the dosage is 0.08 mg/kg. In some embodiments, the dosage is 0.127 mg/kg. In some embodiments, the dosage is 0.13 mg/kg. In some embodiments, the dosage is 0.15 mg/kg. In some embodiments, the dosage is 0.19 mg/kg. In some embodiments, the dosage is 0.247 mg/kg. In some embodiments, the dosage is 0.30 mg/kg. In some embodiments, the dosage is 0.309 mg/kg. In some embodiments, the dosage is 0.386 mg/kg. In some embodiments, the dosage is 0.483 mg/kg. In some embodiments, the dosage is 0.603 mg/kg. In some embodiments, the dosage is 0.754 mg/kg. In some embodiments, the dosage is 0.942 mg/kg. In some embodiments, the dosage is 1.0 mg/kg. In some embodiments, the dosage is 2.0 mg/kg. In some embodiments, the dosage is 3.0 mg/kg. In some preferred embodiments, the anti-CD117 antibody comprises a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 2.
In some preferred embodiments, the antibody comprises a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 9 and a light chain having an amino acid sequence as set forth in SEQ ID NO: 10. In some preferred embodiments, the anti-CD117 antibody comprises an Fc region comprising a D265C mutation (according to EU index). In some preferred embodiments, the anti-CD117 antibody comprises an Fc region comprising a L234A mutation and a L235A mutation (according to EU index). In some preferred embodiments, the anti-CD117 antibody comprises an Fc region comprising a H435A mutation (according to EU index). In some preferred embodiments, the ADC has the structure of formula (I): (Formula I),
or a stereoisomer thereof; wherein: Q is S; Ab is the anti-CD117 antibody; and L-Z is
, wherein
represents the point of attachment to the antibody (Ab) and
represents the point of attachment to the amatoxin. In some preferred embodiments, the anti-CD117 ADC has a structure according to Formula Ia:
(Formula Ia)
In some preferred embodiments, the ADC has the structure of formula (III): (III), or a stereoisomer thereof; wherein: X is S or S(O); L is a linker; Z is a chemical moiety formed by a coupling reaction between a reactive substituent Z' present on L and a reactive substituent present within the anti-CD117 antibody; and
Ab is the anti-CD117 antibody. In some preferred embodiments, the ADC has the structure of formula (IV): (IV), wherein Ab is the anti-CD117 antibody. In some preferred embodiments, the methods and uses described above further comprise a administering a cell transplantation to the human patient. In some preferred embodiments, the cell transplantation comprises a population of stem cells. In some preferred embodiments, the stem cells are allogeneic. In some preferred embodiments, the human patient has a cancer. In some preferred embodiments, the cancer is a leukemia. In some preferred embodiments, the leukemia is relapsed or refractory acute myeloid leukemia. In some preferred embodiments, the human patient has myelodysplasia, e.g., myelodysplasia with excess blasts (MDS-EB). In some preferred embodiments, the cell transplantation comprises genetically modified cells. In some preferred embodiments, the human patient has a hemoglobinapthy or a lysosomal disorder. In some preferred embodiments, the human patient is administered a single dose of the anti-CD117 ADC. In some preferred embodiments, the anti-CD117 ADC is administered to the human patient intravenously. In some preferred embodiments, the patient is administered a second dose of the anti-CD117 ADC upon achieving a partial remission. In some preferred embodiments, the human subject has at least one of the following characteristics: is an adult who is age 18-75 inclusive; has an identified HSCT donor prior to administration of the anti-CD117 ADC; and
has an Eastern Cooperative Oncology Group (ECOG) performance status of <2; has no significant organ dysfunction prior to administration of the anti-CD117 ADC; has no systemic infections prior to administration of the anti-CD117 ADC; has no APL, active CNS leukemia or chloroma prior to administration of the anti-CD117 ADC; or has had washouts for prior anti-leukemic therapies prior to administration of the anti- CD117 ADC. In some preferred embodiments, the human subject does not have at least one of the following characteristics prior to administration of the anti-CD117 ADC: acute promyelocytic leukemia (APL); active central nervous system (CNS) leukemia; chloroma (granulocyte sarcoma); received an HSC transplant within 6 months of being selected for treatment; active graft-versus-host disease (GVHD); active hepatitis B (Hep-B) or hepatitis C (Hep-C) infection; a history of human immunodeficiency virus (HIV); a QTc value >470 msec; has received another investigational drug or device within 30 days; active uncontrolled systemic bacterial, fungal, or viral infection; any systemic antileukemia treatment within 14 days except hydroxyurea; received prior ADC treatment or anti-CD117 antibody treatment; received recent monoclonal antibody therapy within the last 30 days; received recent vaccination within the last 14 days; or Grade 2 or higher electrolyte abnormality at screening. In another embodiment, the present invention provides a method of depleting CD117+ cells in a human subject having a hematological cancer, the method comprising administering an anti-CD117 antibody drug conjugate (ADC) to the human subject having a hematological cancer, thereby depleting CD117+ cells in the subject, wherein the anti-CD117 ADC comprises an anti-CD117 antibody (Ab) conjugated via a linker (L) to an amatoxin (Am), wherein the anti- CD117 ADC has a structure selected from the group consisting of Formula I:
HO
(Formula I), or a stereoisomer thereof; wherein: Q is S; Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:7, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 8; L-Z comprises a non-cleavable linker , wherein represents
the point of attachment to the antibody (Ab) and represents the point of attachment to the amatoxin; formula (III):
(III), or a stereoisomer thereof; wherein: X is S or S(O); L is a linker; Z is a chemical moiety formed by a coupling reaction between a reactive substituent Z' present on L and a reactive substituent present within the anti-CD117 antibody; and Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:7, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 8; and formula (IV):
(IV), wherein Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:7, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 8. In another embodiment, present invention provides an antibody drug conjugate (ADC) comprising an anti-CD117 antibody (Ab) conjugated via a linker (L) to an amatoxin (Am) for use in depleting CD117+ cells in a human subject having a hematological cancer, wherein the anti- CD117 ADC has a structure selected from the group consisting of Formula I:
(Formula I), or a stereoisomer thereof; wherein: Q is S; Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:7, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 8; L-Z is , wherei
n represents the point of attachment to the antibody (Ab) and represents the point of attachment to the amatoxin; formula (III):
(III), or a stereoisomer thereof; wherein: X is S or S(O); L is a linker; Z is a chemical moiety formed by a coupling reaction between a reactive substituent Z' present on L and a reactive substituent present within the anti-CD117 antibody; and Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:7, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 8; and formula (IV):
(IV), wherein Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:7, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 8. In some preferred embodiments, the hematologic cancer is Acute Myeloid Leukemia (AML) or Myelodysplasia-Excess Blasts (MDS-EB). In some preferred embodiments, the AML is CD117+ AML. In some preferred embodiments, the human subject has relapsed or refractory AML (R/R AML). In some preferred embodiments, the human subject has at least one of the following characteristics: is an adult who is age 18-75 inclusive; has an identified HSCT donor prior to administration of the anti-CD117 ADC; and has an Eastern Cooperative Oncology Group (ECOG) performance status of <2; has no significant organ dysfunction prior to administration of the anti-CD117 ADC; has no systemic infections prior to administration of the anti-CD117 ADC; has no APL, active CNS leukemia or chloroma prior to administration of the anti-CD117 ADC; or
has had washouts for prior anti-leukemic therapies prior to administration of the anti- CD117 ADC. In some preferred embodiments, the human subject does not have at least one of the following characteristics prior to administration of the anti-CD117 ADC: acute promyelocytic leukemia (APL); active central nervous system (CNS) leukemia; chloroma (granulocyte sarcoma); received an HSC transplant within 6 months of being selected for treatment; active graft-versus-host disease (GVHD); active hepatitis B (Hep-B) or hepatitis C (Hep-C) infection; a history of human immunodeficiency virus (HIV); a QTc value >470 msec; has received another investigational drug or device within 30 days; active uncontrolled systemic bacterial, fungal, or viral infection; any systemic antileukemia treatment within 14 days except hydroxyurea; received prior ADC treatment or anti-CD117 antibody treatment; received recent monoclonal antibody therapy within the last 30 days; received recent vaccination within the last 14 days; or Grade 2 or higher electrolyte abnormality at screening. In some preferred embodiments, the anti-CD117 ADC is administered to the human subject as a single dose. In some preferred embodiments, the anti-CD117 antibody comprises a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 1, and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 2. In some preferred embodiments, the anti-CD117 antibody comprises an Fc region comprising amino acid substitutions L234A, L235A, D265C and H435A. In some preferred embodiments, the anti-CD117 antibody comprises a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 9 and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 10. In some preferred embodiments, the anti-CD117 ADC has a structure according to Formula Ia:
(Formula Ia) In some preferred embodiments, the anti-CD117 ADC is administered to the human subject at a dose of about 0.02 mg/kg. In some preferred embodiments, the anti-CD117 ADC is administered to the human subject at a dose of about 0.04 mg/kg. In some preferred embodiments, the anti-CD117 ADC is administered to the human subject at a dose of about 0.08 mg/kg. In some preferred embodiments, the anti-CD117 ADC is administered to the human subject at a dose of about 0.076 mg/kg. In some preferred embodiments, the anti-CD117 ADC is administered to the human subject at a dose of about 0.13 mg/kg. In some preferred embodiments, the anti-CD117 ADC is administered to the human subject at a dose of about 0.19 mg/kg. In some preferred embodiments, the human subject is administered a single dose of the anti-CD117 ADC. In some preferred embodiments, the anti-CD117 ADC is administered to the human subject intravenously. In some preferred embodiments, the human subject achieves complete remission of MDS or the hematological cancer. Brief Description of the Figures Fig.1 graphically depicts the results of a non-human primate (NHP) pharmacokinetic assay expressed as the mean (+/-SD) plasma concentration (ng/mL) of an anti-CD117 antibody drug conjugate (i.e., an anti-CD117 antibody conjugated to an amatoxin) as a function of time (i.e., days post-administration; x-axis) in a NHP after a single intravenous administration of the
anti-CD117 antibody drug conjugate at 0.05 mg/kg (triangle), 0.15 mg/kg (square), 0.3 mg/kg (triangle), 0.5 mg/kg (inverted triangle), 1 mg/kg (diamond), and 3 mg/kg (circle) mg/kg. Fig.2 graphically depicts the results of a cell depletion assay expressed as the mean (+/-SD) blood reticulocyte counts (109/L) as a function of time (i.e., days post-administration; x- axis) in a NHP after a single intravenous administration of the anti-CD117 antibody drug conjugate at 0.05 mg/kg (triangle), 0.15 mg/kg (square), 0.3 mg/kg (triangle), 0.5 mg/kg (inverted triangle), 1 mg/kg (diamond), and 3 mg/kg (circle) mg/kg. Fig.3A-B depicts the results of a cell depletion assay in bone marrow. Fig.3A depicts depletion of stem cells in bone marrow expressed as mean (+/-SD) CD34+/CD90+/CD45RA- counts (103/mL) as a function of time (i.e., days post-administration; x-axis) in a NHP after a single intravenous administration of the anti-CD117 antibody drug conjugate at 0.05 mg/kg (triangle), 0.15 mg/kg (square), 0.3 mg/kg (triangle), 0.5 mg/kg (inverted triangle), 1 mg/kg (diamond), and 3 mg/kg (circle) mg/kg. Fig.3B shows the depletion of CD34+/CD90+/CD45RA- stem cells on day 7 post-administration at 0.05 mg/kg, 0.15 mg/kg, 0.3 mg/kg, 0.5 mg/kg, 1 mg/kg, and 3 mg/kg. Fig.4 graphically depicts MGTA-117 concentration (ng/mL) as a function of time (hours). Participants in cohort 1 (0.02 mg/kg) are represented by circles, participants in cohort 2 (0.04 mg/kg) are represented by squares, and participants in cohort 3 (0.08 mg/kg) are represented by triangles. Fig.5 graphically depicts data showing MGTA-117 rapidly bound to CD117+ blast cells in blood. The percentage of blast cell receptor occupancy as a function of time (hours). Participants in cohort 1 (0.02 mg/kg) are represented by circles, participants in cohort 2 (0.04 mg/kg) are represented by squares, and participants in cohort 3 are represented by triangles. Fig.6 graphically depicts data showing MGTA-117 depleted CD117+ blast cells in blood for 3 of the cohorts (cohorts 1, 2, and 3). The percentage change in CD117+ blast cells is shown relative to baseline (0). The maximum percent change for an individual participant at any time point is shown. Fig.7 shows case study results showing that MGTA-117 depleted CD117+ red blood cell progenitors in bone marrow. The figure shows flow cytometry data from blood marrow samples for participant 3 at screening and following MGTA-117 treatment. Plots are gated with a forward scatter for CD34, side scatter for CD71, and sequentially for CD117.The boxed area indicates the CD117+ RBC progenitor cell population.
Fig.8 graphically depicts the absolute percent change from baseline for blast cells in bone marrow. Day 14 results are shown for cohort 1, and day 7 results are shown for cohorts 2 and 3. The results show that MGTA-117 depleted blast cells in the bone marrow. Fig.9 presents details of the treatment plan for a participant from cohort 1. The case study was a 58 year old male with FLT3 mutation and treatment refractory AML. The patient had complete remission (CR) observed to date after a single dose of MGTA-117. Fig.10 presents details of the treatment plan for a participant from cohort 3. The case study was a 73 year old female with ASXL1, BCOR, U2AF1 mutations and treatment refractory MDS. The patient had complete remission (CR) observed to date after a single dose of MGTA- 117. Detailed Description The invention provides targeted conditioning methods comprising administering an effective dose of an anti-CD117 antibody drug conjugate (ADC) comprising anti-CD117 antibody conjugated to an amatoxin, to a patient in need thereof. Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification. It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. As used herein, the term “about” refers to a value that is within 10% above or below the value being described. As used herein, the term “amatoxin” refers to a member of the amatoxin family of peptides which are generally produced by Amanita phalloides mushrooms, or a derivative thereof, such as a variant or derivative thereof capable of inhibiting RNA polymerase II activity. Amatoxins may be isolated from a variety of mushroom species (e.g., Amanita phalloides, Galerina marginata, Lepiota brunneo-incarnata) or may be prepared semi-synthetically or synthetically. A member of this family, α−amanitin, is described in Wieland, Int. J. Pept. Protein Res.1983, 22(3):257-276. A derivative of an amatoxin may be obtained by chemical modification of a naturally occurring compound ("semi-synthetic"), or may be obtained from an
entirely synthetic source. Synthetic routes to various amatoxin derivatives are disclosed in, for example, U.S. Patent No.9,676,702 and in Perrin et al., J. Am. Chem. Soc.2018, 140, p.6513- 6517, each of which is incorporated by reference herein in their entirety with respect to synthetic methods for preparing and derivatizing amatoxins. Amatoxins useful in conjunction with the compositions and methods described herein include compounds such, as, but not limited to, compounds of Formula (I), α-amanitin, β-amanitin, γ-amanitin, ε-amanitin, amanin, amaninamide, amanullin, amanullinic acid, and proamanullin. As described herein, amatoxins may be conjugated to an antibody, or antigen-binding fragment thereof, for instance, by way of a linker moiety (L) (thus forming an ADC). As used herein, the term "antibody" refers to an immunoglobulin molecule that specifically binds to, or is immunologically reactive with, a particular antigen. Generally, antibodies comprise heavy and light chains containing antigen binding regions. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH, and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). As used herein, the term “complementarity determining region” (CDR) refers to a hypervariable region found both in the light chain and the heavy chain variable domains of an antibody. Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. The amino acid positions that delineate a hypervariable region of an antibody can vary, depending on the context and the various definitions known in the art. Some positions within a variable domain may be viewed as hybrid hypervariable positions in that these positions can be deemed to be within a hypervariable region under one set of criteria while being deemed to be outside a hypervariable region under a different set of criteria. One or more of these positions can also be found in extended hypervariable regions. The antibodies described herein may
contain modifications in these hybrid hypervariable positions. The variable domains of native heavy and light chains each contain four framework regions that primarily adopt a β-sheet configuration, connected by three CDRs, which form loops that connect, and in some cases form part of, the β-sheet structure. The CDRs in each chain are held together in close proximity by the framework regions in the order FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 and, with the CDRs from the other antibody chains, contribute to the formation of the target binding site of antibodies (see Kabat et al., Sequences of Proteins of Immunological Interest, National Institute of Health, Bethesda, MD., 1987). In certain embodiments, numbering of immunoglobulin amino acid residues is performed according to the immunoglobulin amino acid residue numbering system of Kabat et al., unless otherwise indicated (although any antibody numbering scheme, including, but not limited to IMGT and Chothia, can be utilized). An "intact" or "full length" antibody, as used herein, refers to an antibody having two heavy (H) chain polypeptides and two light (L) chain polypeptides interconnected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH, and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl- terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. As used herein, the term “antibody drug conjugate” or “conjugate”, refers to a compound formed by the chemical bonding of a reactive functional group of one molecule, such as an antibody, with an appropriately reactive functional group of another molecule, such as a cytotoxin described herein. The foregoing conjugates are also referred to interchangeably herein as a “drug antibody conjugate” and an “ADC”. Conjugates may include a linker between the two molecules bound to one another, e.g., between an antibody and a cytotoxin. Examples of linkers that can be used for the formation of a conjugate include peptide-containing linkers,
such as those that contain naturally occurring or non-naturally occurring amino acids, such as D-amino acids. Linkers can be prepared using a variety of strategies described herein and known in the art. Depending on the reactive components therein, a linker may be cleaved, for example, by enzymatic hydrolysis, photolysis, hydrolysis under acidic conditions, hydrolysis under basic conditions, oxidation, disulfide reduction, nucleophilic cleavage, or organometallic cleavage (see, for example, Leriche et al., Bioorg. Med. Chem., 20:571-582, 2012). As used herein, the term “anti-CD117 antibody” or "an antibody that binds to CD117" refers to an antibody that is capable of binding CD117, e.g., human CD117 (hCD117) with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting CD117. As used herein, the term "consists essentially of," or variations such as "consist essentially of" or "consisting essentially of", indicates the inclusion of any recited integer or group of integers, and the optional inclusion of any recited integer or group of integers that do not materially change the basic or novel properties of the specified method, structure or composition described therein. As used herein, the terms “condition” and “conditioning” refer to processes by which a patient is prepared for receipt of a transplant, e.g., a transplant containing hematopoietic stem cells (HSCs). According to the methods described herein, a patient may be conditioned for hematopoietic stem cell transplant therapy by administration to the patient of an anti-CD117 ADC. Administration of an anti-CD117 ADC to a patient in need of hematopoietic stem cell transplant therapy can promote the engraftment of a hematopoietic stem cell graft, for example, by selectively depleting endogenous hematopoietic stem cells, thereby creating a vacancy filled by an exogenous hematopoietic stem cell transplant. As used herein, the term “hematopoietic stem cells” (“HSCs”) refers to immature blood cells having the capacity to self-renew and to differentiate into mature blood cells containing diverse lineages including but not limited to granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), erythrocytes (e.g., reticulocytes, erythrocytes), thrombocytes (e.g., megakaryoblasts, platelet producing megakaryocytes, platelets), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B-cells and T-cells). Such cells may include CD34+ cells. CD34+ cells are immature cells that express the CD34 cell surface marker. In humans, CD34+ cells are believed to include a subpopulation of cells with the stem cell properties defined above, whereas in mice, HSCs are CD34-. In addition, HSCs also refer to long term repopulating HSCs (LT-HSC) and short term repopulating
HSCs (ST-HSC). LT-HSCs and ST-HSCs are differentiated, based on functional potential and on cell surface marker expression. For example, human HSCs are CD34+, CD38-, CD45RA-, CD90+, CD49F+, and lin- (negative for mature lineage markers including CD2, CD3, CD4, CD7, CD8, CD10, CD11B, CD19, CD20, CD56, CD235A). In mice, bone marrow LT-HSCs are CD34-, SCA-1+, C-kit+, CD135-, Slamfl/CD150+, CD48-, and lin- (negative for mature lineage markers including Ter119, CD11b, Gr1, CD3, CD4, CD8, B220, IL7ra), whereas ST-HSCs are CD34+, SCA-1+, C-kit+, CD135-, Slamfl/CD150+, and lin- (negative for mature lineage markers including Ter119, CD11b, Gr1, CD3, CD4, CD8, B220, IL7ra). In addition, ST-HSCs are less quiescent and more proliferative than LT-HSCs under homeostatic conditions. However, LT- HSC have greater self-renewal potential (i.e., they survive throughout adulthood, and can be serially transplanted through successive recipients), whereas ST-HSCs have limited self- renewal (i.e., they survive for only a limited period of time, and do not possess serial transplantation potential). Any of these HSCs can be used in the methods described herein. ST-HSCs are particularly useful because they are highly proliferative and thus, can more quickly give rise to differentiated progeny. As used herein, patients that are “in need of” a hematopoietic stem cell transplant include patients that exhibit a defect or deficiency in one or more blood cell types, as well as patients having a stem cell disorder, autoimmune disease, cancer, or other pathology described herein. As used herein, the term “recipient” refers to a patient that receives a transplant, such as a transplant containing a population of cells, e.g., hematopoietic stem cells. The transplanted cells administered to a recipient may be, e.g., autologous, syngeneic, or allogeneic cells. As used herein, the terms “subject”, “patient”, and “participant” refer to an organism, such as a human, that receives treatment for a particular disease or condition as described herein. For instance, a patient, such as a human patient, may receive treatment prior to a HSC transplant for depletion of endogenous CD117+ cells. As used herein, the phrase “substantially cleared from the blood” refers to a point in time following administration of a therapeutic agent (such as an anti-CD117 ADC) to a patient when the concentration of the therapeutic agent in a blood sample isolated from the patient is such that the therapeutic agent is not detectable by conventional means (for instance, such that the therapeutic agent is not detectable above the noise threshold of the device or assay used to detect the therapeutic agent). A variety of techniques known in the art can be used to detect ADCs, antibodies, and antibody fragments, such as ELISA-based detection assays known in the art or
described herein. Additional assays that can be used to detect antibodies, or antibody fragments, include immunoprecipitation techniques and immunoblot assays, among others known in the art. As used herein, the phrase "stem cell disorder" broadly refers to any disease, disorder, or condition that may be treated by conditioning a subject's target tissues, and/or by ablating an endogenous stem cell population in a target tissue (e.g., ablating an endogenous hematopoietic stem or progenitor cell population from a subject's bone marrow tissue) and/or by transplanting stem cells in a subject's target tissues. For example, diseases that may be treated using the patient conditioning and/or hematopoietic stem cell transplant methods described herein include, but are not limited to, inherited blood disorders (e.g., sickle cell anemia), or a cancer such as a hematologic cancer, such as leukemia, lymphoma, and myeloma. For instance, the cancer may be acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, multiple myeloma, diffuse large B-cell lymphoma, or non-Hodgkin’s lymphoma. As used herein, the terms “treat” or “treatment” refers to reducing the severity and/or frequency of disease symptoms, eliminating disease symptoms and/or the underlying cause of said symptoms, reducing the frequency or likelihood of disease symptoms and/or their underlying cause, and/or improving or remediating damage caused, directly or indirectly, by disease. Beneficial or desired clinical results include, but are not limited to, the reduction in quantity of a disease-causing cell population, such as a population of cancer cells (e.g., CD117+ leukemic cells). As used herein, the terms "variant" and "derivative" are used interchangeably and refer to naturally-occurring, synthetic, and semi-synthetic analogues of a compound, peptide, protein, or other substance described herein. A variant or derivative of a compound, peptide, protein, or other substance described herein may retain or improve upon the biological activity of the original material. As used herein, the term “coupling reaction” refers to a chemical reaction in which two or more substituents suitable for reaction with one another react so as to form a chemical moiety that joins (e.g., covalently) the molecular fragments bound to each substituent. Coupling reactions include those in which a reactive substituent bound to a fragment that is a cytotoxin, such as a cytotoxin known in the art or described herein, reacts with a suitably reactive substituent bound to a fragment that is an antibody, or antigen-binding fragment thereof, such as an antibody, antigen-binding fragment thereof, or specific anti-CD117 antibody that binds CD117 known in the art or described herein. Examples of suitably reactive substituents include a nucleophile/electrophile pair (e.g., a thiol/haloalkyl pair, an amine/carbonyl pair, or a thiol/α,β-unsaturated carbonyl pair, among others), a diene/dienophile
pair (e.g., an azide/alkyne pair, among others), and the like. Coupling reactions include, without limitation, thiol alkylation, hydroxyl alkylation, amine alkylation, amine condensation, amidation, esterification, disulfide formation, cycloaddition (e.g., [4+2] Diels-Alder cycloaddition, [3+2] Huisgen cycloaddition, among others), nucleophilic aromatic substitution, electrophilic aromatic substitution, and other reactive modalities known in the art or described herein. The term "acyl" as used herein refers to -C(=O)R, wherein R is hydrogen (“aldehyde”), C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C7 carbocyclyl, C6-C20 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryloyl. The term "C1-C12 alkyl" as used herein refers to a straight chain or branched, saturated hydrocarbon having from 1 to 12 carbon atoms. Representative C1-C12 alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while branched C1-C12 alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, and 2-methylbutyl. A C1-C12 alkyl group can be unsubstituted or substituted. The term "alkenyl" as used herein refers to C2-C12 hydrocarbon containing normal, secondary, or tertiary carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp2 double bond. Examples include, but are not limited to: ethylene or vinyl, -allyl, -1-butenyl, -2- butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3- dimethyl-2-butenyl, and the like. An alkenyl group can be unsubstituted or substituted. "Alkynyl" as used herein refers to a C2-C12 hydrocarbon containing normal, secondary, or tertiary carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond. Examples include, but are not limited to acetylenic and propargyl. An alkynyl group can be unsubstituted or substituted. "Aryl" as used herein refers to a C6-C20 carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl and anthracenyl. An aryl group can be unsubstituted or substituted. "Arylalkyl" as used herein refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2- phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2- naphthophenylethan-1-yl and the like. The arylalkyl group comprises 6 to 20 carbon atoms, e.g. the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6
carbon atoms and the aryl moiety is 5 to 14 carbon atoms. An alkaryl group can be unsubstituted or substituted. “Cycloalkyl” as used herein refers to a saturated carbocyclic radical, which may be mono- or bicyclic. Cycloalkyl groups include a ring having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl group can be unsubstituted or substituted. “Cycloalkenyl” as used herein refers to an unsaturated carbocyclic radical, which may be mono- or bicyclic. Cycloalkenyl groups include a ring having 3 to 6 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle. Examples of monocyclic cycloalkenyl groups include 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1- cyclohex-2-enyl, and 1-cyclohex-3-enyl. A cycloalkenyl group can be unsubstituted or substituted. "Heteroaralkyl" as used herein refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heteroaryl radical. Typical heteroarylalkyl groups include, but are not limited to, 2- benzimidazolylmethyl, 2-furylethyl, and the like. The heteroarylalkyl group comprises 6 to 20 carbon atoms, e.g. the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the heteroarylalkyl group is 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S. The heteroaryl moiety of the heteroarylalkyl group may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), for example: a bicyclo[4,5], [5,5], [5,6], or [6,6] system. "Heteroaryl" and "heterocycloalkyl" as used herein refer to an aromatic or non-aromatic ring system, respectively, in which one or more ring atoms is a heteroatom, e.g. nitrogen, oxygen, and sulfur. The heteroaryl or heterocycloalkyl radical comprises 2 to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S. A heteroaryl or heterocycloalkyl may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), for example: a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Heteroaryl and heterocycloalkyl can be unsubstituted or substituted. Heteroaryl and heterocycloalkyl groups are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7,
and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. Examples of heteroaryl groups include by way of example and not limitation pyridyl, thiazolyl, tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, benzotriazolyl, benzisoxazolyl, and isatinoyl. Examples of heterocycloalkyls include by way of example and not limitation dihydroypyridyl, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, piperazinyl, quinuclidinyl, and morpholinyl. By way of example and not limitation, carbon bonded heteroaryls and heterocycloalkyls are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4- pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. By way of example and not limitation, nitrogen bonded heteroaryls and heterocycloalkyls are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3- pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or beta-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1- imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
"Substituted” as used herein and as applied to any of the above alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl, and the like, means that one or more hydrogen atoms are each independently replaced with a substituent. Unless otherwise constrained by the definition of the individual substituent, the foregoing chemical moieties, such as “alkyl”, “alkylene”, “heteroalkyl”, “heteroalkylene”, “alkenyl”, “alkenylene”, “heteroalkenyl”, “heteroalkenylene”, “alkynyl”, “alkynylene”, “heteroalkynyl”, “heteroalkynylene”, “cycloalkyl”, “cycloalkylene”, “heterocyclolalkyl”, heterocycloalkylene”, “aryl,” “arylene”, “heteroaryl”, and “heteroarylene” groups can optionally be substituted. Typical substituents include, but are not limited to, -X, -R, -OH, -OR, -SH, -SR, NH2, -NHR, -N(R)2, -N+(R)3, -CX3, -CN, -OCN, -SCN, - NCO, -NCS, -NO, -NO2, -N3, -NC(=O)H, -NC(=O)R, -C(=O)H, -C(=O)R, -C(=O)NH2, - C(=O)N(R)2, -SO3-, -SO3H, -S(=O)2R, -OS(=O)2OR, -S(=O)2NH2, -S(=O)2N(R)2, -S(=O)R, - OP(=O)(OH)2, -OP(=O)(OR)2, -P(=O)(OR)2, -PO3, -PO3H2, -C(=O)X, -C(=S)R, -CO2H, -CO2R, - CO2-, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NH2, -C(=O)N(R)2, -C(=S)NH2, -C(=S)N(R)2, - C(=NH)NH2, and -C(=NR)N(R)2; wherein each X is independently selected for each occasion from F, Cl, Br, and I; and each R is independently selected for each occasion from C1-C12 alkyl, C6-C20 aryl, C3-C14 heterocycloalkyl or heteroaryl, protecting group and prodrug moiety. Wherever a group is described as "optionally substituted," that group can be substituted with one or more of the above substituents, independently for each occasion. It is to be understood that certain radical naming conventions can include either a mono- radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di- radical. For example, a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as "alkylene," "alkenylene," “arylene,” “heterocycloalkylene,” and the like. Wherever a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated. "Isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereoisomers," and stereoisomers
that are non-superimposable mirror images of each other are termed "enantiomers," or sometimes "optical isomers." A carbon atom bonded to four non-identical substituents is termed a "chiral center." "Chiral isomer" means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed "diastereomeric mixture." When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.1966, 5, 385; errata 511; Cahn et al., Angew. Chem.1966, 78, 413; Cahn and Ingold, J. Chem. Soc.1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ.1964, 41, 116). A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture." The compounds disclosed in this description and in the claims may comprise one or more asymmetric centers, and different diastereomers and/or enantiomers of each of the compounds may exist. The description of any compound in this description and in the claims is meant to include all enantiomers, diastereomers, and mixtures thereof, unless stated otherwise. In addition, the description of any compound in this description and in the claims is meant to include both the individual enantiomers, as well as any mixture, racemic or otherwise, of the enantiomers, unless stated otherwise. When the structure of a compound is depicted as a specific enantiomer, it is to be understood that the coumponds disclosed herein are not limited to that specific enantiomer. Accordingly, enantiomers, optical isomers, and diastereomers of each of the structural formulae of the present disclosure are contemplated herein. In the present specification, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present disclosure includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like, it being understood that not all isomers may have the same level of activity. The compounds may occur in different tautomeric forms. The compounds according to the disclosure are meant to include all tautomeric forms, unless stated otherwise. When the structure of a compound is depicted as a specific tautomer, it is to be understood that the instant disclosure is not limited to that specific tautomer.
The compounds of any formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a compound of the disclosure. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate). The term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a compound of the disclosure. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. The compounds of the disclosure also include those salts containing quaternary nitrogen atoms. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous. Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose. Additionally, the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc. "Solvate" means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in
the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O. A hydrate refers to, for example, a mono- hydrate, a di-hydrate, a tri-hydrate, etc. In addition, a crystal polymorphism may be present for the compounds or salts thereof represented by the formulae disclosed herein. It is noted that any crystal form, crystal form mixture, or anhydride or hydrate thereof, is included in the scope of the present disclosure. Uses of Anti-CD117 Antibdoy Drug Conjugate (ADC) Antibody drug conjugates (ADCs) as described herein can be administered to a human patient (e.g., a human patient suffering from cancer or a human patient in need of hematopoietic stem cell transplant therapy or gene therapy) for conditioning prior to a cell transplantation. In particular, disclosed herein are doses of the anti-CD117 amatoxin drug conjugate that can be used to condition a human patient or deplete CD117+ cells in a human patient in need thereof. In one embodiment, the invention provides a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of about 0.05 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In one embodiment, disclosed herein is a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of about 0.15 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In one embodiment, disclosed herein is a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of about 0.3 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In one embodiment, disclosed herein is a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the
patient a dose of about 0.5 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In one embodiment, disclosed herein is a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of about 1.0 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In another embodiment, disclosed herein is a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of about 3.0 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering to the human patient a dose of about 0.15 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of about 0.3 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of about 0.5 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of about 1.0 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of about 3.0 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, the invention provides a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of 0.02 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In one embodiment, disclosed herein is a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of 0.04 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In one embodiment, disclosed herein is a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of 0.076 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In one embodiment, disclosed herein is a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of 0.127 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In another embodiment, disclosed herein is a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of 0.19 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In a further embodiment, disclosed herein is a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering
to the patient a dose of 0.247 mg/kg of an anti-CD117 antibody drug conjugate (ADC), such that the population of CD117+ cells in the human patient in need thereof, is depleted. In still another embodiment, disclosed herein is a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of 0.309 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells are depleted. In yet a further embodiment, disclosed herein is a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of 0.386 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In one embodiment, disclosed herein is a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of 0.483 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In one embodiment, disclosed herein is a depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of 0.603 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In one embodiment, disclosed herein is a depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of 0.754 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In one embodiment, disclosed herein is a depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of 0.942 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering to the human patient a dose of 0.02 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.04 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.076 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.127 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.190 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.247 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.2 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises
an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.309 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.3 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.386 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.483 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.4 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.603 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant.
In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.6 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.754 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.942 mg/kg of an anti-CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, such that the human patient is conditioned for an HSC transplant. In one embodiment, the invention provides a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of 0.02 mg/kg of an anti-CD117 ADC, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In one embodiment, disclosed herein is a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of 0.04 mg/kg of an anti-CD117 ADC, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In one embodiment, disclosed herein is a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of 0.08 mg/kg of an anti-CD117 ADC, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In one embodiment, disclosed herein is a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of 0.13 mg/kg of an anti-CD117 ADC, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In another embodiment, disclosed herein is a method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering
to the patient a dose of 0.19 mg/kg of an anti-CD117 ADC, such that the population of CD117+ cells in the human patient in need thereof, is depleted. In one embodiment, disclosed herein is a method of conditioning a human patient for a hematopoietic stem cell (HSC) transplant comprising administering to the human patient a dose of 0.02 mg/kg of MGTA-117 such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for a hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.04 mg/kg of an anti-CD117 ADC such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for a hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.08 mg/kg of an anti-CD117 ADC such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for a hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.13 mg/kg of an anti-CD117 ADC such that the human patient is conditioned for an HSC transplant. In one embodiment, disclosed herein is a method of conditioning a human patient for a hematopoietic stem cell (HSC) transplant comprising administering a dose of 0.19 mg/kg of an anti-CD117 ADC such that the human patient is conditioned for an HSC transplant. Accordingly, described herein are methods comprising administering an anti-CD117 antibody drug conjugate to a human patient to selectively deplete CD117+ hematopoietic stem cells (HSCs) from the patient prior to an HSC transplant and/or as treatment for a disease, such as leukemia. The methods disclosed herein represent targeted conditioning, whereby an anti- CD117 ADC is used to selectively deplete hematopoietic stem cells (HSCs) in a human patient in need of an HSC transplant. Using MGTA-117 to specifically target CD117+ HSCs allows for conditioning without the need for myeloablative regimens, such as high-dose or high-intensity chemotherapeutic agents. In the case of gene therapy applications, the methods disclosed herein potentially eliminate the need for chemotherapeutic agents altogether. As described herein, a hematopoietic stem cell (HSC) transplant can be administered to a subject in need of treatment so as to populate or re-populate one or more blood cell types. HSCs generally exhibit multi-potency, and can thus differentiate into multiple different blood lineages including, but not limited to, granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), erythrocytes (e.g., reticulocytes, erythrocytes), thrombocytes (e.g., megakaryoblasts, platelet producing megakaryocytes, platelets), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B-cells
and T-cells). HSCs are additionally capable of self-renewal, and can thus give rise to daughter cells that have equivalent potential as the mother cell, and also feature the capacity to be reintroduced into a transplant recipient whereupon they home to the hematopoietic stem cell niche and re-establish productive and sustained hematopoiesis. Hematopoietic stem cells (HSCs) can thus be administered to a patient defective or deficient in one or more cell types of the hematopoietic lineage in order to re-constitute the defective or deficient population of cells in vivo, thereby treating the pathology associated with the defect or depletion in the endogenous blood cell population. The compositions and methods described herein can thus be used to treat a non-malignant hemoglobinopathy (e.g., a hemoglobinopathy such as sickle cell anemia, thalassemia, Fanconi anemia, aplastic anemia, and Wiskott-Aldrich syndrome). Additionally or alternatively, the compositions and methods described herein can be used to treat an immunodeficiency, such as a congenital immunodeficiency. Additionally or alternatively, the compositions and methods described herein can be used to treat a malignancy or proliferative disorder, such as a hematologic cancer or myeloproliferative disease. In the case of cancer treatment, the compositions and methods described herein may be administered to a patient so as to deplete a population of endogenous hematopoietic stem cells prior to hematopoietic stem cell transplantation therapy, in which case the transplanted cells can home to a niche created by the endogenous cell depletion step and establish productive hematopoiesis. This, in turn, can re-constitute a population of cells depleted during cancer cell eradication, such as during systemic chemotherapy. Exemplary hematological cancers that can be treated using the compositions and methods described herein include, without limitation, acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, multiple myeloma, diffuse large B-cell lymphoma, and non-Hodgkin’s lymphoma, as well as other cancerous conditions, including neuroblastoma. In addition, the methods disclosed herein can be used to treat cancers directly, such as cancers characterized by cells that are CD117+. For instance, MGTA-117 can be used to treat leukemia, particularly in patients that exhibit CD117+ leukemic cells. By depleting CD117+ cancerous cells, such as leukemic cells, the compositions and methods described herein can be used to treat various cancers directly. Exemplary cancers that may be treated in this fashion include hematological cancers, such as acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, multiple myeloma, diffuse large B-cell
lymphoma, and non-Hodgkin’s lymphoma. Methods for the depletion of CD117+ cells are further described in WO2017/219029, which is hereby incorporated by reference in its entirety. The methods disclosed herein may be used to selectively deplete CD117-positive cells in a human patient having acute AML or myelodysplasia-excess blasts (MDS-EB). In one embodiment, the AML is CD117+ AML or the MDS-EB is MDS-EB with 5% to 19% marrow myeloblasts and/or 2% to 19% peripheral blasts for MDS-EB. In one embodiment, the MDS-EB is CD117+ MDS-EB. The human patient may be an adult, e.g., age 18 to 75. The human patient may have failed previous therapy prior to administration of an anti- CD117 ADC for selective depletion of CD117+ HSCs. For example, the human patient may have acute AML and may have previously failed primary AML induction. In another example, the human patient may have MDS-EB and have previously failed or be refractory to HMA. HSCs transplanted into a subject in need thereof may be obtained from the patient themselves (i.e., autologous) or a donor (e.g., allogeneic). Examples of HSC donors include a related donor, an unrelated donor, a haplo-identical transplant donor, or an umbilical blood donor. As used herein, the term "allogeneic", when used in the context of transplantation, is used to define cells (or tissue or an organ) that are transplanted from a donor to a recipient of the same species but who is genetically different. Thus, the term "allogeneic cells" refers to cell types that are genetically distinct between two individuals, yet belong to the same species, e.g., human. Typically, the term "allogeneic" is used to define cells, such as stem cells, that are transplanted from a donor to an unrelated recipient of the same species. As used herein, the term "autologous" refers to cells or a graft where the donor and recipient are the same subject. In one embodiment, the HSCs transplanted to the human subject following administration of an anti-CD117 ADC are autologous but are genetically modified, e.g., modified to correct a gene mutation that results in a disease, e.g., sickle cell anemia. In certain embodiments, a human patient who is administered MGTA-117 in accordance with the methods disclosed herein, has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2; has an adequate baseline hepatic function (e.g., alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤2 x upper limit of normal (ULN), and serum bilirubin ≤1.5 x ULN); has an estimated creatinine clearance ≥60 mL/min; and/or has adequate cardiac function as demonstrated by cardiac left ventricular ejection fraction ≥40%.
In one embodiment, prior to the human patient receiving MGTA-117, toxicities from prior therapies must have resolved to less than or equal to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grade 1 or baseline (except alopecia and hematological). In certain embodiments, a human patient who is administered MGTA-117 in accordance with the methods disclosed herein does not have acute promyelocytic leukemia (APL); does not have a known active central nervous system (CNS) leukemia or chloroma (granulocyte sarcoma); has not received HSCT within 6 months of administration of MGTA-117; has not received chimeric antigen-receptor cell therapies within 6 months prior to dosing; does not have active graft-versus-host disease (GVHD); does not have active hepatitis B (Hep-B) or hepatitis C (Hep-C) infection or a history of human immunodeficiency virus (HIV); does not have a QTc value >470 msec; has not received another investigational drug or device within 30 days of administration of MGTA-117; does not have any clinically significant medical condition; does not have active uncontrolled systemic bacterial, fungal, or viral infection; does not have a history of serious allergic reactions; has not had systemic antileukemia treatment within 14 days of anti- CD117 administration, except hydroxyurea, which is permitted until 24 hours prior to MGTA-117 dosing; has not received prior ADC treatment or anti-CD117 antibody treatment; has not received recent monoclonal antibody therapy within 30 days prior to MGTA-117 administration; has not received recent vaccination within the last 14 days of MGTA-117 administration; and/or does not have a Grade 2 or higher electrolyte abnormality at screening. Methods described herein can be used to treat cancers, such as cancers characterized by cells that are CD117+. For instance, the compositions and methods described herein can be used to treat leukemia, particularly in patients that exhibit CD117+ leukemic cells. By depleting CD117+ cancerous cells, such as leukemic cells, the compositions and methods described herein can be used to treat various cancers directly. Exemplary cancers that may be treated in this fashion include hematological cancers, such as acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, multiple myeloma, diffuse large B-cell lymphoma, and non-Hodgkin's lymphoma. In certain embodiments, the cancer is a hematological cancer. Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that build up in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age. The symptoms of AML are
caused by replacement of normal bone marrow with leukemic cells, which causes a drop in red blood cells, platelets, and normal white blood cells. As an acute leukemia, AML progresses rapidly and may be fatal within weeks or months if left untreated. In one embodiment, the anti- CD117 ADCs described herein are used to treat AML in a human patient in need thereof. In certain embodiments the anti-CD117 ADC treatment depletes AML cells in the treated subjects. In some embodiments 50% or more of the AML cells are depleted. In other embodiments, 60% or more of the AML cells are depleted, or 70% or more of the AML cells are depleted, or 80% of more or 90% or more, or 95% or more of the AML cells are depleted. In certain embodiments, the methods disclosed herein are useful for treating a human subject having a hematological cancer, such as leukemia or myelodysplastic syndrome. Examples of leukemia that may be treated using the methods and compositions disclosed herein include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, or chronic lymphocytic leukemia. In addition, hematopoietic stem cell transplant therapy can be administered to a subject in need of treatment so as to populate or re-populate one or more blood cell types. Hematopoietic stem cells generally exhibit multi-potency, and can thus differentiate into multiple different blood lineages including, but not limited to, granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), erythrocytes (e.g., reticulocytes, erythrocytes), thrombocytes (e.g., megakaryoblasts, platelet producing megakaryocytes, platelets), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B-cells and T-cells). Hematopoietic stem cells are additionally capable of self-renewal, and can thus give rise to daughter cells that have equivalent potential as the mother cell, and also feature the capacity to be reintroduced into a transplant recipient whereupon they home to the hematopoietic stem cell niche and re-establish productive and sustained hematopoiesis. Hematopoietic stem cells can thus be administered to a patient defective or deficient in one or more cell types of the hematopoietic lineage in order to re-constitute the defective or deficient population of cells in vivo, thereby treating the pathology associated with the defect or depletion in the endogenous blood cell population. The compositions and methods described herein can thus be used to treat a non-malignant hemoglobinopathy (e.g., a hemoglobinopathy selected from the group consisting of sickle cell anemia, thalassemia, Fanconi anemia, aplastic anemia, and Wiskott-Aldrich syndrome). Additionally or alternatively, the compositions and methods described herein can be used to treat an immunodeficiency, such as a congenital immunodeficiency. Additionally or alternatively, the compositions and methods described herein
can be used to treat an acquired immunodeficiency (e.g., an acquired immunodeficiency selected from the group consisting of HIV and AIDS). The compositions and methods described herein can be used to treat a metabolic disorder (e.g., a metabolic disorder selected from the group consisting of glycogen storage diseases, mucopolysaccharidoses, Gaucher's Disease, Hurlers Disease, sphingolipidoses, and metachromatic leukodystrophy). Additional diseases that can be treated with the compositions and methods described herein include, without limitation, lysosomal disorders, such as Gaucher disease, Krabbe disease, Metachromatic leukodystrophy (MLD), Mucopolysaccharidosis (MPS), Niemann-Pick disease, and Tay-Sachs disease. In certain embodiments, the transplanted cells are genetically modified in a manner to treat or cure the disease, a hemoglobinapathy or a lysosomal disease. Other diseases and conditions that can be treated using the methods disclosed herein are provided in U.S. Patent No.10,899,843, which is incorporated by reference herein. Anti-CD117 ADCs described herein can be administered to a patient (e.g., a human patient suffering from cancer, an autoimmune disease, or in need of hematopoietic stem cell transplant therapy) in a variety of dosage forms. For instance, anti-CD117 antibodies, antigen-binding fragments thereof, or ADCs described herein can be administered to a patient suffering from cancer, an autoimmune disease, or in need of hematopoietic stem cell transplant therapy in the form of an aqueous solution, such as an aqueous solution containing one or more pharmaceutically acceptable excipients. The aqueous solution may be sterilized using techniques known in the art. Using the methods disclosed herein, a physician of skill in the art can administer to a human patient in need of hematopoietic stem cell transplant therapy an anti-CD117 ADC capable of binding CD117 expressed by hematopoietic stem cells. In this fashion, a population of endogenous hematopoietic stem cells can be depleted prior to administration of an exogenous hematopoietic stem cell graft so as to promote engraftment of the hematopoietic stem cell graft. The anti-CD117 ADC can s be administered to the patient, for example, by intravenous administration, prior to transplantation of exogenous hematopoietic stem cells (such as autologous, syngeneic, or allogeneic hematopoietic stem cells) to the patient. Following the conclusion of conditioning therapy, the patient may then receive an infusion (e.g., an intravenous infusion) of exogenous hematopoietic stem cells, such as from the same physician that performed the conditioning therapy or from a different physician. The physician may administer the patient an infusion of autologous, syngeneic, or allogeneic hematopoietic stem cells, for instance, at a dosage of from 1 x 103 to 1 x 109 hematopoietic stem cells/kg. The physician may
monitor the engraftment of the hematopoietic stem cell transplant, for example, by withdrawing a blood sample from the patient and determining the increase in concentration of hematopoietic stem cells or cells of the hematopoietic lineage (such as megakaryocytes, thrombocytes, platelets, erythrocytes, mast cells, myeloblasts, basophils, neutrophils, eosinophils, microglia, granulocytes, monocytes, osteoclasts, antigen-presenting cells, macrophages, dendritic cells, natural killer cells, T-lymphocytes, and B-lymphocytes) following administration of the transplant. This analysis may be conducted, for example, from about 1 hour to about 6 months, or more, following hematopoietic stem cell transplant therapy (e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, or more). A finding that the concentration of hematopoietic stem cells or cells of the hematopoietic lineage has increased (e.g., by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 500%, or more) following the transplant therapy relative to the concentration of the corresponding cell type prior to transplant therapy provides one indication that treatment with the anti-CD117 antibody, an antigen-binding fragment thereof, or an ADC has successfully promoted engraftment of the transplanted hematopoietic stem cell graft. Engraftment of hematopoietic stem cell transplants due to the administration of an anti- CD117 antibody, or antigen-binding fragments thereof, or ADCs, can manifest in a variety of empirical measurements. For instance, engraftment of transplanted hematopoietic stem cells can be evaluated by assessing the quantity of competitive repopulating units (CRU) present within the bone marrow of a patient following administration of an antibody or antigen-binding fragment thereof capable of binding capable of binding an antigen expressed by hematopoietic stem cells (e.g., CD117 (e.g., GNNK+ CD117) and subsequent administration of a hematopoietic stem cell transplant. Additionally, one can observe engraftment of a hematopoietic stem cell transplant by incorporating a reporter gene, such as an enzyme that catalyzes a chemical reaction yielding a
fluorescent, chromophoric, or luminescent product, into a vector with which the donor hematopoietic stem cells have been transfected and subsequently monitoring the corresponding signal in a tissue into which the hematopoietic stem cells have homed, such as the bone marrow. One can also observe hematopoietic stem cell engraftment by evaluation of the quantity and survival of hematopoietic stem and progenitor cells, for instance, as determined by fluorescence activated cell sorting (FACS) analysis methods known in the art. Engraftment can also be determined by measuring white blood cell counts in peripheral blood during a post-transplant period, and/or by measuring recovery of marrow cells by donor cells in a bone marrow aspirate sample. Engraftment of hematopoietic stem cell transplants due to the administration of an anti- CD117 ADC described herein can manifest in a variety of empirical measurements. For instance, engraftment of transplanted hematopoietic stem cells can be evaluated by assessing the quantity of competitive repopulating units (CRU) present within the bone marrow of a patient following administration of an antibody or antigen-binding fragment thereof capable of binding an antigen described herein and subsequent administration of a hematopoietic stem cell transplant. Additionally, one can observe engraftment of a hematopoietic stem cell transplant by incorporating a reporter gene, such as an enzyme that catalyzes a chemical reaction yielding a fluorescent, chromophoric, or luminescent product, into a vector with which the donor hematopoietic stem cells have been transfected and subsequently monitoring the corresponding signal in a tissue into which the hematopoietic stem cells have homed, such as the bone marrow. One can also observe hematopoietic stem cell engraftment by evaluation of the quantity and survival of hematopoietic stem and progenitor cells, for instance, as determined by fluorescence activated cell sorting (FACS) analysis methods known in the art. Engraftment can also be determined by measuring white blood cell counts in peripheral blood during a post- transplant period, and/or by measuring recovery of marrow cells by donor cells in a bone marrow aspirate sample. The present invention includes dosing regimens that reduce adverse events and toxicity using ADCs that are capable of binding CD117 expressed by, e.g., an HSC. The sections that follow provide a description of anti-CD117 ADCs that can be administered to a patient in need of a transplantation, e.g., hematopoietic stem cell transplant, in order to promote engraftment of hematopoietic stem cells, as well as methods of administering such therapeutics to a patient prior to hematopoietic stem cell transplantation. Anti-CD117 Antibodies
Amino acid sequences of anti-CD117 antibodies that can be used both in the RO assays described herein and in the therapeutics compositions described herein are described in U.S. Patent No.10,899,843, which is incorporated by reference herein. In one embodiment, an anti-CD117 antibody, or antigen binding fragment thereof, comprises a heavy chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 3, 4, and 5, respectively, and comprises a light chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 6, 7, and 8, respectively. In one embodiment, an anti-CD117 antibody, or antigen binding fragment thereof, comprises a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 2, and a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 1. The heavy chain variable region (VH) amino acid sequence of Ab85 is provided below as SEQ ID NO: 1. The VH CDR amino acid sequences of Ab85 are underlined below and are as follows: NYWIG (VH CDR1; SEQ ID NO: 3); IINPRDSDTRYRPSFQG (VH CDR2; SEQ ID NO: 4); and HGRGYEGYEGAFDI (VH CDR3; SEQ ID NO: 5). Ab85 VH sequence
(SEQ ID NO: 1) The light chain variable region (VL) amino acid sequence of Ab85 is provided below as SEQ ID NO: 2. The VL CDR amino acid sequences of Ab85 are underlined below and are as follows: RSSQGIRSDLG (VL CDR1; SEQ ID NO: 6); DASNLET (VL CDR2; SEQ ID NO: 7); and QQANGFPLT (VL CDR3; SEQ ID NO: 8). Ab85 VL sequence
(SEQ ID NO: 2)
In one embodiment, an anti-CD117 antibody, or antigen binding fragment thereof, comprises a heavy chain having the amino acid sequence as set forth as SEQ ID NO: 9, and a light chain having an amino acid sequence set forth as SEQ ID NO: 10. In certain embodiments, an anti-CD117 antibody is an IgG1 isotype. The anti-CD117 antibody comprising any of the sequences set forth in the Table below can be an intact antibody and/or an IgG1 or an IgG4 isotype. In one embodiment, the anti-CD117 antibody, or binding fragment thereof, comprises a variant Fc region, wherein said variant Fc region comprises at least one amino acid modification relative to a wild-type Fc region, such that said molecule has an altered affinity for an FcgammaR. Certain amino acid positions within the Fc region are known through crystallography studies to make a direct contact with FcγR. Specifically, amino acids 234-239 (hinge region), amino acids 265-269 (B/C loop), amino acids 297-299 (C'/E loop), and amino acids 327-332 (F/G) loop. (see Sondermann et al., 2000 Nature, 406: 267-273). For example, amino acid substitutions at amino acid positions 234 and 235 of the Fc region have been identified as decreasing affinity of an IgG antibody for binding to an Fc receptor, particularly an Fc gamma receptor (FcγR). In one embodiment, an anti-CD117 antibody described herein comprises an Fc region comprising an amino acid substituion at L234 and/or L235, e.g., L234A and L235A (EU index). Thus, the anti-CD117 antibodies described herein may comprise variant Fc regions comprising modification of at least one residue that makes a direct contact with an FcγR based on structural and crystallographic analysis. In one embodiment, the Fc region of the anti-CD117 antibody (or Fc containing fragment thereof) comprises an amino acid substitution at amino acid 265 according to the EU index as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, NH1, MD (1991), expressly incorporated herein by references. The "EU index as in Kabat" or “EU index” refers to the numbering of the human IgG1 EU antibody and is used herein in reference to Fc amino acid positions unless otherwise indicated. In one embodiment, the Fc region comprises a D265A mutation. In one embodiment, the Fc region comprises a D265C mutation. In some embodiments, the Fc region of the anti-CD117 antibody (or fragment thereof) comprises an amino acid substitution at amino acid 234 according to the EU index as in Kabat. In one embodiment, the Fc region comprises a L234A mutation. In some embodiments, the Fc region of the anti-CD117 antibody (or fragment thereof) comprises an amino acid substitution at amino acid 235 according to the EU index as in Kabat. In one embodiment, the Fc region
comprises a L235A mutation. In yet another embodiment, the Fc region comprises a L234A and L235A mutation. In a further embodiment, the Fc region comprises a D265C, L234A, and L235A mutation. In certain aspects a variant IgG Fc domain comprises one or more amino acid substitutions resulting in decreased or ablated binding affinity for an FcgammaR and/or C1q as compared to the wild-type Fc domain not comprising the one or more amino acid substitutions. Fc binding interactions are essential for a variety of effector functions and downstream signaling events including, but not limited to, antibody dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). Accordingly, in certain aspects, an antibody comprising a modified Fc region (e.g., comprising a L234A, L235A, and a D265C mutation) has substantially reduced or abolished effector functions. Affinity to an Fc region can be determined using a variety of techniques known in the art, for example but not limited to, equilibrium methods (e.g., enzyme-linked immunoabsorbent assay (ELISA); KinExA, Rathanaswami et al. Analytical Biochemistry, Vol.373:52-60, 2008; or radioimmunoassay (RIA)), or by a surface plasmon resonance assay or other mechanism of kinetics-based assay (e.g., BIACORETM analysis or OctetTM analysis (forteBIO)), and other methods such as indirect binding assays, competitive binding assays fluorescence resonance energy transfer (FRET), gel electrophoresis and chromatography (e.g., gel filtration). These and other methods may utilize a label on one or more of the components being examined and/or employ a variety of detection methods including but not limited to chromogenic, fluorescent, luminescent, or isotopic labels. A detailed description of binding affinities and kinetics can be found in Paul, W. E., ed., Fundamental Immunology, 4th Ed., Lippincott-Raven, Philadelphia (1999), which focuses on antibody-immunogen interactions. One example of a competitive binding assay is a radioimmunoassay comprising the incubation of labeled antigen with the antibody of interest in the presence of increasing amounts of unlabeled antigen, and the detection of the antibody bound to the labeled antigen. The affinity of the antibody of interest for a particular antigen and the binding off-rates can be determined from the data by scatchard plot analysis. Competition with a second antibody can also be determined using radioimmunoassays. In this case, the antigen is incubated with antibody of interest conjugated to a labeled compound in the presence of increasing amounts of an unlabeled second antibody. In one embodiment, an anti-CD117 antibody described herein comprises an Fc region comprising L235A, L235A, and D265C (EU index). The antibodies of the invention may be further engineered to further modulate antibody half-life by introducing additional Fc mutations,
such as those described for example in (Dall'Acqua et al. (2006) J Biol Chem 281: 23514-24), (Zalevsky et al. (2010) Nat Biotechnol 28: 157-9), (Hinton et al. (2004) J Biol Chem 279: 6213- 6), (Hinton et al. (2006) J Immunol 176: 346-56), (Shields et al. (2001) J Biol Chem 276: 6591- 604), (Petkova et al. (2006) Int Immunol 18: 1759-69), (Datta-Mannan et al. (2007) Drug Metab Dispos 35: 86-94), (Vaccaro et al. (2005) Nat Biotechnol 23: 1283-8), (Yeung et al. (2010) Cancer Res 70: 3269-77) and (Kim et al. (1999) Eur J Immunol 29: 2819-25), and include positions 250, 252, 253, 254, 256, 257, 307, 376, 380, 428, 434 and 435. Exemplary mutations that may be made singularly or in combination are T250Q, M252Y, 1253A, S254T, T256E, P2571, T307A, D376V, E380A, M428L, H433K, N434S, N434A, N434H, N434F, H435A and H435R mutations. Thus, in one embodiment, the Fc region comprises a mutation resulting in a decrease in half life. An antibody having a short half-life may be advantageous in certain instances where the antibody is expected to function as a short-lived therapeutic, e.g., the conditioning step described herein where the antibody is administered followed by HSCs. Ideally, the antibody would be substantially cleared prior to delivery of the HSCs, which also generally express CD117 but are not the target of the anti-CD117 antibody, unlike the endogenous stem cells. In one embodiment, the Fc region comprises a mutation at position 435 (EU index according to Kabat). In one embodiment, the mutation is an H435A mutation. In one embodiment, the anti-CD117 antibody or ADC described herein has a half-life of equal to or less than 24 hours, equal to or less than 22 hours, equal to or less than 20 hours, equal to or less than 18 hours, equal to or less than 16 hours, equal to or less than 14 hours, equal to or less than 13 hours, equal to or less than 12 hours, or equal to or less than 11 hours. In one embodiment, the half-life of the antibody is 11 hours to 24 hours; 12 hours to 22 hours; 10 hours to 20 hours; 8 hours to 18 hours; or 14 hours to 24 hours. Antibodies may be produced using recombinant methods and compositions, e.g., as described in U.S. Pat. No.4,816,567. In one embodiment, isolated nucleic acid encoding an anti-CD117 antibody described herein is provided. Such nucleic acid may encode an amino acid sequence comprising the VL and/or an amino acid sequence comprising the VH of the antibody (e.g., the light and/or heavy chains of the antibody). In a further embodiment, one or more vectors (e.g., expression vectors) comprising such nucleic acid are provided. In a further embodiment, a host cell comprising such nucleic acid is provided. In one such embodiment, a host cell comprises (e.g., has been transformed with): (1) a vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and an amino acid
sequence comprising the VH of the antibody, or (2) a first vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising the VH of the antibody. In one embodiment, the host cell is eukaryotic, e.g. a Chinese Hamster Ovary (CHO) cell or lymphoid cell (e.g., Y0, NS0, Sp20 cell). In one embodiment, a method of making an anti- CLL-1 antibody is provided, wherein the method comprises culturing a host cell comprising a nucleic acid encoding the antibody, as provided above, under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium). For recombinant production of an anti-CD117 antibody, nucleic acid encoding an antibody, e.g., as described above, is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell. Such nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody). Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein. For example, antibodies may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Pat. Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, N.J., 2003), pp.245-254, describing expression of antibody fragments in E. coli.) After expression, the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified. Vertebrate cells may also be used as hosts. For example, mammalian cell lines that are adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J. Gen Virol.36:59 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N.Y. Acad. Sci.383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR- CHO cells (Urlaub et al., Proc. Natl. Acad. Sci.
USA 77:4216 (1980)); and myeloma cell lines such as Y0, NS0 and Sp2/0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol.248 (B. K. C. Lo, ed., Humana Press, Totowa, N.J.), pp. 255-268 (2003). In one embodiment, the anti-CD117 antibody, or antigen binding fragment thereof, comprises variable regions having an amino acid sequence that is at least 95%, 96%, 97% or 99% identical to the SEQ ID Nos disclosed herein. Alternatively, the anti-CD117 antibody, or antigen binding fragment thereof, comprises CDRs comprising the SEQ ID Nos disclosed herein with framework regions of the variable regions described herein having an amino acid sequence that is at least 95%, 96%, 97% or 99% identical to the SEQ ID Nos disclosed in the Tables herein. TABLE 1: ANTI-CD117 ANTIBODY SEQUENCES
Anti-CD117 Antibody Drug Conjugates Anti-CD117 antibodies, and antigen-binding fragments thereof, described herein, e.g., Ab85, can be conjugated (linked) to a cytotoxin, i.e., an amatoxin. In some embodiments, the cytotoxic molecule is conjugated to a cell internalizing anti-CD117 antibody, or antigen-binding fragment thereof as disclosed herein such that following the cellular uptake of the antibody, or fragment thereof, the cytotoxin may access its intracellular target and mediate hematopoietic cell death. An example of such an antibody is Ab85. ADCs of the present invention therefore may be of the general formula Ab-(Z-L-D)n, wherein an anti-CD117 antibody or antigen-binding fragment thereof (Ab) is conjugated (covalently linked) to a linker (L), and through a chemical moiety (Z), to a cytotoxic moiety (“drug,” D) which is an amatoxin. Accordingly, the anti-CD117 antibody may be conjugated to a number of drug moieties as indicated by integer n, which represents the average number of amatoxins per antibody. Any number of amatoxins can be conjugated to the antibody, e.g., about 1, about 2, about 3, about 4, about 5, about 6, about 7, or about 8. In some embodiments, n is from 1 to 4. In some embodiments, n is from 1 to 3. In some embodiments, n is about 2. In some embodiments, n is about 1. In one embodiment, two amatoxins are conjugated to an anti-CD117 antibody. For example, two amatoxins can be conjugated to an anti-CD117 antibody via cysteine residues in the Fc region of the anti-CD117 antibody.
The average number of drug moieties per antibody in preparations of ADC from conjugation reactions may be characterized by conventional means such as mass spectroscopy, ELISA assay, and HPLC. The quantitative distribution of ADC in terms of n may also be determined. In some instances, separation, purification, and characterization of homogeneous ADC where n is a certain value from ADC with other drug loadings may be achieved by means such as reverse phase HPLC or electrophoresis. For some anti-CD117 ADCs, n may be limited by the number of attachment sites on the antibody. For example, where the attachment is a cysteine thiol, an antibody may have only one or several cysteine thiol groups, or may have only one or several sufficiently reactive thiol groups through which a linker may be attached. Generally, antibodies do not contain many free and reactive cysteine thiol groups which may be linked to a drug moiety; primarily, cysteine thiol residues in antibodies exist as disulfide bridges. In certain embodiments, an antibody may be reduced with a reducing agent such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP), under partial or total reducing conditions, to generate reactive cysteine thiol groups. In certain embodiments, higher drug loading, e.g., n>5, may cause aggregation, insolubility, toxicity, or loss of cellular permeability of certain antibody-drug conjugates. In certain embodiments, fewer than the theoretical maximum number of drug moieties are conjugated to an antibody during a conjugation reaction. An antibody may contain, for example, lysine residues that do not react with the drug-linker intermediate or linker reagent, as discussed below. Only the most reactive lysine groups may react with an amine-reactive linker reagent. In certain embodiments, an antibody is subjected to denaturing conditions to reveal reactive nucleophilic groups such as lysine or cysteine. The loading (drug/antibody ratio) of an ADC may be controlled in different ways, e.g., by: (i) limiting the molar excess of drug-linker intermediate or linker reagent relative to antibody, (ii) limiting the conjugation reaction time or temperature, (iii) partial or limiting reductive conditions for cysteine thiol modification, (iv) engineering by recombinant techniques the amino acid sequence of the antibody such that the number and position of cysteine residues is modified for control of the number and/or position of linker-drug attachments. Amatoxins Described herein are uses of anti-CD117 antibody drug conjugates comprising an anti- CD117 anitbody conjugated to an amatoxin. Amatoxins useful in conjunction with the
compositions and methods described herein include compounds according to, but are not limited to, formula (I), (I) wherein: R1 is H, OH, or ORA; R2 is H, OH, or ORB; RA and RB, when present, together with the oxygen atoms to which they are bound, combine to form an optionally substituted 5-membered heterocycloalkyl group; R3 is H or RD; R4 is H, OH, ORD, or RD; R5 is H, OH, ORD, or RD; R6 is H, OH, ORD, or RD; R7 is H, OH, ORD, or RD; R8 is OH, NH2, or ORD; R9 is H, OH, or ORD; X is -S-, -S(O)-, or -SO2-; and RD is optionally substituted alkyl (e.g., C1-C6 alkyl), optionally substituted heteroalkyl (e.g., C1-C6 heteroalkyl), optionally substituted alkenyl (e.g., C2-C6 alkenyl), optionally substituted heteroalkenyl (e.g., C2-C6 heteroalkenyl), optionally substituted alkynyl (e.g., C2-C6 alkynyl), optionally substituted heteroalkynyl (e.g., C2-C6 heteroalkynyl), optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
For instance, in one embodiment, amatoxins useful in conjunction with the compositions and methods described herein include compounds according to formula (Ia) (Ia), wherein R4, R5, X, and R8 are each as defined above. For instance, in one embodiment, amatoxins useful in conjunction with the compositions and methods described herein include compounds according to formula (Ib), below: (Ib) wherein: R1 is H, OH, or ORA; R2 is H, OH, or ORB; RA and RB, when present, together with the oxygen atoms to which they are bound, combine to form an optionally substituted 5-membered heterocycloalkyl group; R3 is H or RD; R4 is H, OH, ORD, or RD;
R5 is H, OH, ORD, or RD; R6 is H, OH, ORD, or RD; R7 is H, OH, ORD, or RD; R8 is OH, NH2, or ORD; R9 is H, OH, or ORD; X is -S-, -S(O)-, or -SO2-; and RD is optionally substituted alkyl (e.g., C1-C6 alkyl), optionally substituted heteroalkyl (e.g., C1-C6 heteroalkyl), optionally substituted alkenyl (e.g., C2-C6 alkenyl), optionally substituted heteroalkenyl (e.g., C2-C6 heteroalkenyl), optionally substituted alkynyl (e.g., C2-C6 alkynyl), optionally substituted heteroalkynyl (e.g., C2-C6 heteroalkynyl), optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In one embodiment, amatoxins useful in conjunction with the compositions and methods described herein also include compounds according to formula (Ic), below: (Ic) wherein: R1 is H, OH, or ORA; R2 is H, OH, or ORB; RA and RB, when present, together with the oxygen atoms to which they are bound, combine to form an optionally substituted 5-membered heterocycloalkyl group; R3 is H or RD; R4 is H, OH, ORD, or RD; R5 is H, OH, ORD, or RD; R6 is H, OH, ORD, or RD;
R7 is H, OH, ORD, or RD; R8 is OH, NH2, or ORD; R9 is H, OH, or ORD; X is -S-, -S(O)-, or -SO2-; and RD is optionally substituted alkyl (e.g., C1-C6 alkyl), optionally substituted heteroalkyl (e.g., C1-C6 heteroalkyl), optionally substituted alkenyl (e.g., C2-C6 alkenyl), optionally substituted heteroalkenyl (e.g., C2-C6 heteroalkenyl), optionally substituted alkynyl (e.g., C2-C6 alkynyl), optionally substituted heteroalkynyl (e.g., C2-C6 heteroalkynyl), optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. Synthetic methods of making amatoxin are described in U.S. Patent No.9,676,702, which is incorporated by reference herein. Many positions on amatoxins or derivatives thereof can serve as the position to covalently bond the linking moiety L, and, hence the antibodies or antigen-binding fragments thereof. In some embodiments, the cytotoxin in the ADC is an amatoxin or derivative thereof according to formula (I, Ia, Ib, or Ic). In one embodiment, the ADC is represented by the general formula Ab-Z-L-Am, wherein Ab is an antibody or antigen-binding fragment thereof that binds CD117, L is a linker, Z is a chemical moiety, and Am is an amatoxin. In certain embodiments, the ADC having the general formula Ab-Z-L-Am, is represented by formula (II): (II)
wherein: R1 is H, OH, ORA, or ORC; R2 is H, OH, ORB, or ORC; RA and RB, when present, together with the oxygen atoms to which they are bound, combine to form a 5-membered heterocycloalkyl group; R3 is H, RC, or RD; R4 is H, OH, ORC, ORD, RC, or RD; R5 is H, OH, ORC, ORD, RC, or RD; R6 is H, OH, ORC, ORD, RC, or RD; R7 is H, OH, ORC, ORD, RC, or RD; R8 is OH, NH2, ORC, ORD, NHRC, or NRCRD; R9 is H, OH, ORC, or ORD; X is -S-, -S(O)-, or -SO2-; RC is–-L-Z-Ab, RD is C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 heteroalkenyl, C2-C6 alkynyl, C2-C6 heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or a combination thereof, wherein each C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 heteroalkenyl, C2-C6 alkynyl, C2-C6 heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with from 1 to 5 substituents independently selected for each occasion from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, and nitro. L is a linker, such as optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, (C=O); or comprises a peptide or a dipeptide; or comprises –((CH2)mO)n(CH2)m–, where m and n are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; or a combination of any thereof; and Z is a chemical moiety formed from a coupling reaction between a reactive substituent Z' present on L and a reactive substituent present within an antibody, or antigen-binding fragment thereof, that binds CD117 (such as GNNK+ CD117).
In some embodiments, Am contains exactly one RC substituent. In some embodiments, the cytotoxin is an amatoxin or derivative thereof and the ADC Ab-Z-L-Am is represented by formula (II), wherein: R1 and R2 are each independently H or OH; R3 is RC; R4, R6, and R7 are each H; R5 is H, OH, or OC1-C6 alkyl; R8 is OH or NH2; R9 is H or OH; X is -S-, -S(O)-, or -SO2-; and RC and RD are as defined above. Such amatoxin-linker conjugates are described, for example, in U.S. Patent Application Publication No.2014/0294865, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the cytotoxin is an amatoxin or derivative thereof and the ADC Ab-Z-L-Am is represented by formula (II), wherein: R1 and R2 are each independently H or OH; R3, R6, and R7 are each H; R4 and R5 are each independently H, OH, ORC, or RC; R8 is OH or NH2; R9 is H or OH; X is -S-, -S(O)-, or -SO2-; and RC and RD are as defined above. Such amatoxin-linker conjugates are described, for example, in U.S. Patent Application Publication No.2015/0218220, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the cytotoxin is an amatoxin or derivative thereof and the ADC Ab-Z-L-Am is represented by formula (II), wherein: R1 and R2 are each independently H or OH; R3, R6, and R7 are each H; R4 and R5 are each independently H or OH; R8 is OH, NH2, ORC, or NHRC; R9 is H or OH;
X is -S-, -S(O)-, or -SO2-; and RC and RD are as defined above. Such amatoxin conjugates are described, for example, in U.S. Patent Nos.9,233,173 and 9,399,681, the disclosures of each of which are incorporated herein by reference in their entirety. In one embodiment, the CD117 antibodies, or antigen-binding fragments, described herein may be bound to an amatoxin so as to form an ADC represented by the formula Ab-Z-L- Am, wherein Ab is the CD117 antibody, or antigen-binding fragment thereof, L is a linker, Z is a chemical moiety and Am is an amatoxin, each as described herein. In some instances, the anti-CD117 ADC has the structure of formula (III):
(III), wherein: X is S or –S(O)-; L is a linker; Z is a chemical moiety formed by a coupling reaction between a reactive substituent present on L and a reactive substituent present within the anti-CD117 antibody; and Ab is the anti-CD117 antibody. In some embodiments, L is a non-cleavable linker; In some embodiments, an anti-CD117 ADC described herein has the structure of formula (IIIa):
(IIIa). or formula (IIIb): (IIIb).
In some instances, the anti-CD117 ADC has the structure of formula (IV):
(IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Ab is the anti-CD117 antibody. In some instances, the anti-CD117 ADC has the structure of formula (IVa): (IVa) a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Ab is the anti-CD117 antibody. In some instances, the anti-CD117 ADC has the structure of formula (IVb):
(IVb) a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Ab is the anti-CD117 antibody. Amatoxins that may be used in the ADCs described herein are also provided in WO 2020/216947, which is incorporated by reference herein. Linkers A variety of linkers can be used to conjugate antibodies, or antigen-binding fragments, as described herein (e.g., antibodies, or antigen-binding fragments thereof, that recognize and bind CD117 (such as GNNK+ CD117) with a cytotoxic molecule, i.e., amatoxin. The term “Linker" as used herein means a divalent chemical moiety comprising a covalent bond or a chain of atoms that covalently attaches an anti-CD117 antibody or fragment thereof (Ab) to a drug moiety (D) to form antibody-drug conjugates (ADC) of formula II. Suitable linkers have two reactive termini, one for conjugation to an antibody and the other for conjugation to a cytotoxin. The antibody conjugation reactive terminus of the linker (reactive moiety, Z′) is typically a site that is capable of conjugation to the antibody through a cysteine thiol or lysine amine group on the antibody, and so is typically a thiol-reactive group such as a double bond (as in maleimide) or a leaving group such as a chloro, bromo, iodo, or an R- sulfanyl group, or an amine-reactive group such as a carboxyl group; while the cytotoxin conjugation reactive terminus of the linker is typically a site that is capable of conjugation to the cytotoxin. Non-limiting examples for linker-cytotoxin conjugation include, for example, formation of an amide bond with a basic amine or carboxyl group on the cytotoxin, via a carboxyl or basic amine group on the linker, respectively, or formation of an ether or the like, via alkylation of an OH group on the cytotoxin, via e.g., a leaving group on the linker. In some embodiments, cytotoxin-linker conjugation is through formation of an amide bond with a basic amine or carboxyl group on the cytotoxin, and so the reactive substituent on the linker is respectively a
carboxyl or basic amine group. When the term "linker" is used in describing the linker in conjugated form, one or both of the reactive termini will be absent (such as reactive moiety Z′, having been converted to chemical moiety Z) or incomplete (such as being only the carbonyl of the carboxylic acid) because of the formation of the bonds between the linker and/or the cytotoxin, and between the linker and/or the antibody or antigen-binding fragment thereof. Such conjugation reactions are described further herein below. In some embodiments, the linker is cleavable under intracellular conditions, such that cleavage of the linker releases the drug unit from the antibody in the intracellular environment. In yet other embodiments, the linker unit is not cleavable and the drug is released, for example, by antibody degradation. The linkers useful for the present ADCs are preferably stable extracellularly, prevent aggregation of ADC molecules and keep the ADC freely soluble in aqueous media and in a monomeric state. Before transport or delivery into a cell, the ADC is preferably stable and remains intact, i.e. the antibody remains linked to the drug moiety. The linkers are stable outside the target cell and may be cleaved at some efficacious rate inside the cell. An effective linker will: (i) maintain the specific binding properties of the antibody; (ii) allow intracellular delivery of the conjugate or drug moiety; (iii) remain stable and intact, i.e. not cleaved, until the conjugate has been delivered or transported to its targeted site; and (iv) maintain a cytotoxic, cell-killing effect or a cytostatic effect of the cytotoxic moiety. Stability of the ADC may be measured by standard analytical techniques such as mass spectroscopy, HPLC, and the separation/analysis technique LC/MS. Covalent attachment of the antibody and the drug moiety requires the linker to have two reactive functional groups, i.e. bivalency in a reactive sense. Bivalent linker reagents which are useful to attach two or more functional or biologically active moieties, such as peptides, nucleic acids, drugs, toxins, antibodies, haptens, and reporter groups are known, and methods have been described their resulting conjugates (Hermanson, G. T. (1996) Bioconjugate Techniques; Academic Press: New York, p.234-242). Suitable cleavable linkers include those that may be cleaved, for instance, by enzymatic hydrolysis, photolysis, hydrolysis under acidic conditions, hydrolysis under basic conditions, oxidation, disulfide reduction, nucleophilic cleavage, or organometallic cleavage (see, for example, Leriche et al., Bioorg. Med. Chem., 20:571-582, 2012, the disclosure of which is incorporated herein by reference as it pertains to linkers suitable for covalent conjugation). Suitable cleavable linkers may include, for example, chemical moieties such as a hydrazine, a disulfide, a thioether or a dipeptide.
Linkers hydrolyzable under acidic conditions include, for example, hydrazones, semicarbazones, thiosemicarbazones, cis-aconitic amides, orthoesters, acetals, ketals, or the like. (See, e.g., U.S. Pat. Nos.5,122,368; 5,824,805; 5,622,929; Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123; Neville et al., 1989, Biol. Chem.264:14653-14661, the disclosure of each of which is incorporated herein by reference in its entirety as it pertains to linkers suitable for covalent conjugation. Such linkers are relatively stable under neutral pH conditions, such as those in the blood, but are unstable at below pH 5.5 or 5.0, the approximate pH of the lysosome. Linkers cleavable under reducing conditions include, for example, a disulfide. A variety of disulfide linkers are known in the art, including, for example, those that can be formed using SATA (N-succinimidyl-S-acetylthioacetate), SPDP (N-succinimidyl-3-(2- pyridyldithio)propionate), SPDB (N-succinimidyl-3-(2-pyridyldithio)butyrate) and SMPT (N- succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyl-dithio)toluene), SPDB and SMPT (See, e.g., Thorpe et al., 1987, Cancer Res.47:5924-5931; Wawrzynczak et al., In Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (C. W. Vogel ed., Oxford U. Press, 1987. See also U.S. Pat. No.4,880,935, the disclosure of each of which is incorporated herein by reference in its entirety as it pertains to linkers suitable for covalent conjugation. Additional linkers suitable for the synthesis of drug-antibody conjugates conjugates as described herein include those capable of releasing a cytotoxin by a 1,6-elimination process (a "self-immolative" group), such as p-aminobenzyl alcohol (PABC), p-aminobenzyl (PAB), 6- maleimidohexanoic acid, pH-sensitive carbonates, and other reagents described in Jain et al., Pharm. Res.32:3526-3540, 2015, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the linker includes a self-immolative group such as the afore- mentioned PAB or PABC (para-aminobenzyloxycarbonyl), which are disclosed in, for example, Carl et al., J. Med. Chem. (1981) 24:479-480; Chakravarty et al (1983) J. Med. Chem.26:638- 644; US 6214345; US20030130189; US20030096743; US6759509; US20040052793; US6218519; US6835807; US6268488; US20040018194; W098/13059; US20040052793; US6677435; US5621002; US20040121940; W02004/032828). Other such chemical moieties capable of this process (“self-immolative linkers”) include methylene carbamates and heteroaryl groups such as aminothiazoles, aminoimidazoles, aminopyrimidines, and the like. Linkers containing such heterocyclic self-immolative groups are disclosed in, for example, U.S. Patent
Publication Nos.20160303254 and 20150079114, and U.S. Patent No.7,754,681; Hay et al. (1999) Bioorg. Med. Chem. Lett.9:2237; US 2005/0256030; de Groot et al (2001) J. Org. Chem. 66:8815-8830; and US 7223837. Linkers susceptible to enzymatic hydrolysis can be, e.g., a peptide-containing linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease. One advantage of using intracellular proteolytic release of the therapeutic agent is that the agent is typically attenuated when conjugated and the serum stabilities of the conjugates are typically high. In some embodiments, the peptidyl linker is at least two amino acids long or at least three amino acids long. Exemplary amino acid linkers include a dipeptide, a tripeptide, a tetrapeptide or a pentapeptide. Examples of suitable peptides include those containing amino acids such as Valine, Alanine, Citrulline (Cit), Phenylalanine, Lysine, Leucine, and Glycine. Amino acid residues which comprise an amino acid linker component include those occurring naturally, as well as minor amino acids and non- naturally occurring amino acid analogs, such as citrulline. Exemplary dipeptides include valine- citrulline (vc or val-cit) and alanine-phenylalanine (af or ala-phe). Exemplary tripeptides include glycine-valine-citrulline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly). In some embodiments, the linker includes a dipeptide such as Val-Cit, Ala-Val, or Phe-Lys, Val-Lys, Ala- Lys, Phe-Cit, Leu-Cit, Ile-Cit, Phe-Arg, or Trp-Cit. Linkers containing dipeptides such as Val-Cit or Phe-Lys are disclosed in, for example, U.S. Pat. No.6,214,345, the disclosure of which is incorporated herein by reference in its entirety as it pertains to linkers suitable for covalent conjugation. In some embodiments, the linker includes a dipeptide selected from Val-Ala and Val-Cit. In some embodiments, a dipeptide is used in combination with a self-immolative linker. Linkers suitable for use herein further may include one or more groups selected from C1-C6 alkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, C2-C6 heteroalkenylene, C2-C6 alkynylene, C2-C6 heteroalkynylene, C3-C6 cycloalkylene, heterocycloalkylene, arylene, heteroarylene, and combinations thereof, each of which may be optionally substituted. Non-limiting examples of such groups include (CH2)n, (CH2CH2O)n, and –(C=O)(CH2)n – units, wherein n is an integer from 1-6, independently selected for each occasion. In some embodiments, each C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 heteroalkenyl, C2-C6 alkynyl, C2-C6 heteroalkynyl, C3-C6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may be optionally substituted with from 1 to 5 substituents independently selected for each occasion from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino,
aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, and nitro. In some embodiments, each C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 heteroalkenyl, C2-C6 alkynyl, C2-C6 heteroalkynyl, C3-C6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may optionally be interrupted by one or more heteroatoms selected from O, S and N. In some embodiments, each C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 heteroalkenyl, C2-C6 alkynyl, C2-C6 heteroalkynyl, C3-C6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may optionally be interrupted by one or more heteroatoms selected from O, S and N and may be optionally substituted with from 1 to 5 substituents independently selected for each occasion from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto, and nitro. Suitable linkers may contain groups having solubility enhancing properties. Linkers including the (CH2CH2O)p unit (polyethylene glycol, PEG), for example, can enhance solubility, as can alkyl chains substituted with amino, sulfonic acid, phosphonic acid or phosphoric acid residues. Linkers including such moieties are disclosed in, for example, U.S. Patent Nos. 8,236,319 and 9,504,756, the disclosure of each of which is incorporated herein by reference in its entirety as it pertains to linkers suitable for covalent conjugation. Further solubility enhancing groups include, for example, acyl and carbamoyl sulfamide groups, having the structure: wherein a is 0 or 1; and R10 is selected from the group consisting of hydrogen, C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C1-C24 (hetero)aryl groups, C1-C24 alkyl(hetero)aryl groups and C1-C24 (hetero)arylalkyl groups, the C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups, each of which may be optionally substituted and/or optionally interrupted by one or more heteroatoms selected from
O, S and NR11R12, wherein R11 and R12 are independently selected from the group consisting of hydrogen and C1-C4 alkyl groups; or R10 is a cytotoxin, wherein the cytotoxin is optionally connected to N via a spacer moiety. Linkers containing such groups are described, for example, in U.S. Patent No.9,636,421 and U.S. Patent Application Publication No.2017/0298145, the disclosures of which are incorporated herein by reference in their entirety as they pertain to linkers suitable for covalent conjugation to cytotoxins and antibodies or antigen-binding fragments thereof. In some embodiments, the linker comprises a ((CH2)mO) n(CH2)m– group where n and m are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and a heteroaryl group, wherein the heteroaryl group is a triazole. In some embodiments, the ((CH2)mO) n(CH2)m– group and triazole together comprise , where n is from 1 to 10, and the wavy lines indicate attachment points to additional linker components, the chemical moiety Z, or the amatoxin. Other linkers that may be used in the methods and compositions described herein are described in US 2019/0144504, which is incorporated by reference herein. In some embodiments, the linker may include one or more of a hydrazine, a disulfide, a thioether, a dipeptide, a p-aminobenzyl (PAB) group, a heterocyclic self-immolative group, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 heteroalkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C2-C6 heteroalkynyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, acyl, -(C=O)-, or -(CH2CH2O)n- group, wherein n is an integer from 1-6. One of skill in the art will recognize that one or more of the groups listed may be present in the form of a bivalent (diradical) species, e.g., C1-C6 alkylene and the like. In some embodiments, the linker L comprises the moiety *-L1L2-**, wherein: L1 is absent or is -(CH2)mNR13C(=O)-, -(CH2)mNR13-, -(CH2)mX3(CH2)m-,
L2 is absent or is -(CH2)m-, -NR13(CH2)m-, -(CH2)mNR13C(=O)(CH2)m-, -X4, - (CH2)mNR13C(=O)X4, - (CH2)mNR13C(=O)-, -((CH2)mO)n(CH2)m-, -((CH2)mO)n(CH2)mX3(CH2)m-, - NR13((CH2)mO)nX3(CH2)m-, -NR13((CH2)mO)n(CH2)mX3(CH2)m-, -X1X2C(=O)(CH2)m-, - (CH2)m(O(CH2)m)n-, -(CH2)mNR13(CH2)m-, -(CH2)mNR13C(=O)(CH2)mX3(CH2)m-, - (CH2)mC(=O)NR13(CH2)mNR13C(=O)(CH2)m-, -(CH2)mC(=O)-, - (CH2)mNR13(CH2)mC(=O)X2X1C(=O)-, -(CH2)mX3(CH2)mC(=O)X2X1C(=O)-, - (CH2)mC(=O)NR13(CH2)m-, -(CH2)mC(=O)NR13(CH2)mX3(CH2)m-, - (CH2)mX3(CH2)mNR13C(=O)(CH2)m-, -(CH2)mX3(CH2)mC(=O)NR13(CH2)m-, - (CH2)mO)n(CH2)mNR13C(=O)(CH2)m-, -(CH2)mC(=O)NR13(CH2)m(O(CH2)m)n-, - (CH2)m(O(CH2)m)nC(=O)-, -(CH2)mNR13(CH2)mC(=O)-, -(CH2)mC(=O)NR13(CH2)mNR13C(=O)-, - (CH2)m(O(CH2)m)nX3(CH2)m-, - (CH2)mX3((CH2)mO)n(CH2)m-, -(CH2)mX3(CH2)mC(=O)-, - (CH2)mC(=O)NR13(CH2)mO)n(CH2)mX3(CH2)m-, - (CH2)mX3(CH2)m(O(CH2)m)nNR13C(=O)(CH2)m-, - (CH2)mX3(CH2)m(O(CH2)m)nC(=O)-, -(CH2)mX3(CH2)m(O(CH2)m)n-, - (CH2)mC(=O)NR13(CH2)mC(=O)-, -(CH2)mC(=O)NR13(CH2)m(O(CH2)m)nC(=O)-, - ((CH2)mO)n(CH2)mNR13C(=O)(CH2)m-, -(CH2)mC(=O)NR13(CH2)mC(=O)NR13(CH2)m-, - (CH2)mNR13C(=O)(CH2)mNR13C(=O)(CH2) -(CH2)mX3(CH2)mC(=O)NR13-, -(CH2)mC(=O)NR13-, - (CH2)mX3-, -C(R13)2(CH2)m-, -(CH2)mC(R13)2NR13-, -(CH2)mC(=O)NR13(CH2)mNR13-, - (CH2)mC(=O)NR13(CH2)mNR13C(=O)NR13-, -(CH2)mC(=O)X2X1C(=O)-, - C(R13)2(CH2)mNR13C(=O)(CH2)m-, -(CH2)mC(=O)NR13(CH2)mC(R13)2NR13-, - C(R13)2(CH2)mX3(CH2)m-, -(CH2)mX3(CH2)mC(R13)2NR13-, -C(R13)2(CH2)mOC(=O)NR13(CH2)m-, - (CH2)mNR13C(=O)O(CH2)mC(R13)2NR13-, -(CH2)mX3(CH2)mNR13-, - (CH2)mX3(CH2)m(O(CH2)m)nNR13-, -(CH2)mNR13-, -(CH2)mC(=O)NR13(CH2)m(O(CH2)m)nNR13 -, - (CH2)m(O(CH2)m)nNR13-, -(CH2CH2O)n(CH2)m-, -(CH2)m(OCH2CH2)n; -(CH2)mO(CH2)m-, - (CH2)mS(=O)2-, - (CH2)mC(=O)NR13(CH2)mS(=O)2-, -(CH2)mX3(CH2)mS(=O)2-, -(CH2)mX2X1C(=O)-, -(CH2)m(O(CH2)m)nC(=O)X2X1C(=O)-, -(CH2)m(O(CH2)m)nX2X1C(=O)-, - (CH2)mX3(CH2)mX2X1C(=O)-, -(CH2)mX3(CH2)m(O(CH2)m)nX2X1 C(=O)-, - (CH2)mX3(CH2)mC(=O)NR13(CH2)mNR13C(=O)-, -(CH2)mX3(CH2)mC(=O)NR13(CH2)mC(=O)-, -
(CH2)mX3(CH2)mC(=O)NR13(CH2)m(O(CH2)m)nC(=O)-, -(CH2)mC(=O)X2X1C(=O)NR13(CH2)m-, - (CH2)mX3(O(CH2)m)nC(=O)-, -(CH2)mNR13C(=O)((CH2)mO)n(CH2)m-, - (CH2)m(O(CH2)m)nC(=O)NR13(CH2)m-, -(CH2)mNR13C(=O)NR13(CH2)m- or - (CH2)mX3(CH2)mNR13C(=O)-; wherein
; wherein R13 is independently selected for each occasion from H and C1-C6 alkyl; m is independently selected for each occasion from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; n is independently selected for each occasion from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14; and wherein the single asterisk (*) indicates the attachment point to the cytotoxin (e.g., an amatoxin), and the double asterisk (**) indicates the attachment point to the reactive substituent Z' or chemical moiety Z, with the proviso that L1 and L2 are not both absent. In some embodiments, the linker includes a p-aminobenzyl group (PAB). In one embodiment, the p-aminobenzyl group is disposed between the cytotoxic drug and a protease cleavage site in the linker. In one embodiment, the p-aminobenzyl group is part of a p- aminobenzyloxycarbonyl unit. In one embodiment, the p-aminobenzyl group is part of a p- aminobenzylamido unit. In some embodiments, the linker comprises PAB, Val-Cit-PAB, Val-Ala- PAB, Val-Lys(Ac)-PAB, Phe-Lys-PAB, Phe-Lys(Ac)-PAB, D-Val-Leu-Lys, Gly-Gly-Arg, Ala-Ala- Asn-PAB, or Ala-PAB. In some embodiments, the linker comprises a combination of one or more of a peptide, oligosaccharide, -(CH2)n-, -(CH2CH2O)n-, PAB, Val-Cit-PAB, Val-Ala-PAB, Val-Lys(Ac)-PAB, Phe-Lys-PAB, Phe-Lys(Ac)-PAB, D-Val-Leu-Lys, Gly-Gly-Arg, Ala-Ala-Asn-PAB, or Ala-PAB. In one specific embodiment, the linker comprises PAB-Ala-Val-propionyl, represented by the structure wherein the wavy lines indicate attachment points to the cytotoxin and the reactive moiety Z′. In another specific embodiment, the linker comprises PAB-Cit-Val-propionyl, represented by the structure
wherein the wavy lines indicate attachment points to the cytotoxin and the reactive moiety Z′. Such PAB-dipeptide-propionyl linkers are disclosed in, e.g., Patent Application Publication No. WO2017/149077, which is incorporated by reference herein in its entirety. In certain embodiments, the linker of the ADC is maleimidocaproyl-Val-Ala-para- aminobenzyl (mc-Val-Ala-PAB). In certain embodiments, the linker of the ADC is maleimidocaproyl-Val-Cit-para- aminobenzyl (mc-vc-PAB). In some embodiments, the linker comprises . In some embodiments, the linker comprises MCC (4-[N-maleimidomethyl]cyclohexane-1- carboxylate). In some embodiments, the linker comprises a -(CH2)n- unit, wherein n is an integer from 2 to 6. In some embodiments, the linker comprises a -(C=O)(CH2)n- unit, wherein n is an integer from 1-6. Linkers that can be used to conjugate an antibody, or antigen-binding fragment thereof, to a cytotoxic agent include those that are covalently bound to the cytotoxic agent on one end of the linker and, on the other end of the linker, contain a chemical moiety formed from a coupling reaction between a reactive substituent present on the linker and a reactive substituent present within the antibody, or antigen-binding fragment thereof, that binds CD117 (such as GNNK+ CD117). Reactive substituents that may be present within an antibody, or antigen-binding fragment thereof, that binds CD117 (such as GNNK+ CD117) include, without limitation, hydroxyl moieties of serine, threonine, and tyrosine residues; amino moieties of lysine residues; carboxyl moieties of aspartic acid and glutamic acid residues; and thiol moieties of cysteine
residues, as well as propargyl, azido, haloaryl (e.g., fluoroaryl), haloheteroaryl (e.g., fluoroheteroaryl), haloalkyl, and haloheteroalkyl moieties of non-naturally occurring amino acids. Examples of linkers useful for the synthesis of drug-antibody conjugates conjugates include those that contain electrophiles, such as Michael acceptors (e.g., maleimides), activated esters, electron-deficient carbonyl compounds, and aldehydes, among others, suitable for reaction with nucleophilic substituents present within antibodies or antigen-binding fragments, such as amine and thiol moieties. For instance, linkers suitable for the synthesis of drug- antibody conjugates include, without limitation, succinimidyl 4-(N-maleimidomethyl)- cyclohexane-L-carboxylate (SMCC), N- succinimidyl iodoacetate (SIA), sulfo-SMCC, m- maleimidobenzoyl-N-hydroxysuccinimidyl ester (MBS), sulfo-MBS, and succinimidyl iodoacetate, among others described, for instance, Liu et al., 18:690-697, 1979, the disclosure of which is incorporated herein by reference as it pertains to linkers for chemical conjugation. Additional linkers include the non-cleavable maleimidocaproyl linkers, which are particularly useful for the conjugation of microtubule-disrupting agents such as auristatins, are described by Doronina et al., Bioconjugate Chem.17:14-24, 2006, the disclosure of which is incorporated herein by reference as it pertains to linkers for chemical conjugation. It will be recognized by one of skill in the art that any one or more of the chemical groups, moieties and features disclosed herein may be combined in multiple ways to form linkers useful for conjugation of the antibodies and cytotoxins as disclosed herein. Further linkers useful in conjunction with the compositions and methods described herein, are described, for example, in U.S. Patent Application Publication No.2015/0218220, the disclosure of which is incorporated herein by reference in its entirety. Linkers useful in conjunction with the antibody-drug described herein include, without limitation, linkers containing chemical moieties formed by coupling reactions as depicted in Table 2, below. Curved lines designate points of attachment to the antibody, or antigen-binding fragment, and the cytotoxic molecule, respectively. Table 2. Exemplary chemical moieties Z formed by coupling reactions in the formation of antibody-drug
One of skill in the art will recognize that a reactive substituent Z' attached to the linker and a reactive substituent on the antibody or antigen-binding fragment thereof, are engaged in the covalent coupling reaction to produce the chemical moiety Z, and will recognize the reactive substituent Z'. Therefore, antibody-drug conjugates useful in conjunction with the methods described herein may be formed by the reaction of an antibody, or antigen-binding fragment thereof, with a linker or cytotoxin-linker conjugate, as described herein, the linker or cytotoxin- linker conjugate including a reactive substituent Z', suitable for reaction with a reactive substituent on the antibody, or antigen-binding fragment thereof, to form the chemical moiety Z. In some embodiments, Z' is -NR13C(=O)CH=CH2, -N3, -SH, -S(=O)2(CH=CH2), -
(CH2)2S(=O)2(CH=CH2), -NR13S(=O)2(CH=CH2), -NR13C(=O)CH2R14, -NR13C(=O)CH2Br, - NR13C(=O)CH2I, -NHC(=O)CH2Br, -NHC(=O)CH2I, -ONH2, -C(O)NHNH2, -CO2H, -NH2, - NH(C=O), -NC(=S),
R13 is independently selected for each occasion from H and C1-C6 alkyl;
R14 is -S(CH2)nCHR15NHC(=O)R13;
R15 is R13 or -C(=O)OR13;
R16 is independently selected for each occasion from H, Ci-Ce alkyl, F, Cl, and -OH;
R17 is independently selected for each occasion from H, C1-C6 alkyl, F, Cl, -NH2, -OCH3, -OCH2CH3, -N(CH3)2, -CN, -NO2 and-OH; and R18 is independently selected for each occasion from H, C1-C6 alkyl, F, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C1-C4 alkoxy substituted with - C(=O)OH, and C1-C4 alkyl substituted with -C(=O)OH. Examples of suitably reactive substituents on the linker and antibody or antigen-binding fragment thereof include a nucleophile/electrophile pair (e.g., a thiol/haloalkyl pair, an amine/carbonyl pair, or a thiol/ α,β -unsaturated carbonyl pair, and the like), a diene/dienophile pair (e.g., an azide/alkyne pair, or a diene/ α,β-unsaturated carbonyl pair, among others), and the like. Coupling reactions between the reactive substitutents to form the chemical moiety Z include, without limitation, thiol alkylation, hydroxyl alkylation, amine alkylation, amine or hydroxylamine condensation, hydrazine formation, amidation, esterification, disulfide formation, cycloaddition (e.g., [4+2] Diels-Alder cycloaddition, [3+2] Huisgen cycloaddition, among others), nucleophilic aromatic substitution, electrophilic aromatic substitution, and other reactive modalities known in the art or described herein. Preferably, the linker contains an electrophilic functional group for reaction with a nucleophilic functional group on the antibody, or antigen- binding fragment thereof. Reactive substituents that may be present within an antibody, or antigen-binding fragment thereof, as disclosed herein include, without limitation, nucleophilic groups such as (i) N-terminal amine groups, (ii) side chain amine groups, e.g. lysine, (iii) side chain thiol groups, e.g. cysteine, and (iv) sugar hydroxyl or amino groups where the antibody is glycosylated. Reactive substituents that may be present within an antibody, or antigen-binding fragment thereof, as disclosed herein include, without limitation, hydroxyl moieties of serine, threonine, and tyrosine residues; amino moieties of lysine residues; carboxyl moieties of aspartic acid and glutamic acid residues; and thiol moieties of cysteine residues, as well as propargyl, azido, haloaryl (e.g., fluoroaryl), haloheteroaryl (e.g., fluoroheteroaryl), haloalkyl, and haloheteroalkyl moieties of non-naturally occurring amino acids. In some embodiments, the reactive substituents present within an antibody, or antigen-binding fragment thereof as disclosed herein include, are amine or thiol moieties. Certain antibodies have reducible interchain disulfides, i.e. cysteine bridges. Antibodies may be made reactive for conjugation with linker reagents by treatment with a reducing agent such as DTT (dithiothreitol). Each cysteine bridge will thus form, theoretically, two reactive thiol nucleophiles. Additional nucleophilic groups can be introduced into antibodies through the reaction of lysines with 2-iminothiolane (Traut's reagent) resulting in
conversion of an amine into a thiol. Reactive thiol groups may be introduced into the antibody (or fragment thereof) by introducing one, two, three, four, or more cysteine residues (e.g., preparing mutant antibodies comprising one or more non-native cysteine amino acid residues). U.S. Pat. No.7,521,541 teaches engineering antibodies by introduction of reactive cysteine amino acids. In some embodiments, the reactive moiety Z' attached to the linker is a nucleophilic group which is reactive with an electrophilic group present on an antibody. Useful electrophilic groups on an antibody include, but are not limited to, aldehyde and ketone carbonyl groups. The heteroatom of a nucleophilic group can react with an electrophilic group on an antibody and form a covalent bond to the antibody. Useful nucleophilic groups include, but are not limited to, hydrazide, oxime, amino, hydroxyl, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide. In some embodiments, Z is the product of a reaction between reactive nucleophilic substituents present within the antibodies, or antigen-binding fragments thereof, such as amine and thiol moieties, and a reactive electrophilic substituent Z'. For instance, Z' may be a Michael acceptor (e.g., maleimide), activated ester, electron-deficient carbonyl compound, or an aldehyde, among others. Several representative and non-limiting examples of reactive substituents Z' and the resulting chemical moieties Z are provided in Table 3. Table 3. Complementary reactive substituents and chemical moieties
For instance, linkers suitable for the synthesis of ADCs of the disclosure include, without limitation, reactive substituents Z′ such as maleimide or haloalkyl groups. These may be attached to the linker by reagents such as succinimidyl 4-(N-maleimidomethyl)-cyclohexane-L- carboxylate (SMCC), N- succinimidyl iodoacetate (SIA), sulfo-SMCC, m-maleimidobenzoyl-N- hydroxysuccinimidyl ester (MBS), sulfo-MBS, and succinimidyl iodoacetate, among others described, in for instance, Liu et al., 18:690-697, 1979, the disclosure of which is incorporated herein by reference as it pertains to linkers for chemical conjugation. In some embodiments, the reactive substituent Z′ attached to linker L is a maleimide, azide, or alkyne. An example of a maleimide-containing linker is the non-cleavable maleimidocaproyl-based linker. In some embodiments, the reactive substituent Z′ is –(C=O)- or -NH(C=O)-, such that the linker may be joined to the antibody, or antigen-binding fragment thereof, by an amide or urea moiety, respectively, resulting from reaction of the –(C=O)- or -NH(C=O)- group with an amino group of the antibody or antigen-binding fragment thereof.
In some embodiments, the reactive substituent is an N-maleimidyl group, halogenated N-alkylamido group, sulfonyloxy N-alkylamido group, carbonate group, sulfonyl halide group, thiol group or derivative thereof, alkynyl group comprising an internal carbon-carbon triple bond, (het-ero)cycloalkynyl group, bicyclo[6.1.0]non-4-yn-9-yl group, alkenyl group comprising an internal carbon-carbon double bond, cycloalkenyl group, tetrazinyl group, azido group, phosphine group, nitrile oxide group, nitrone group, nitrile imine group, diazo group, ketone group, (O-alkyl)hydroxylamino group, hydrazine group, halogenated N-maleimidyl group, 1,1-bis (sulfonylmethyl)methylcarbonyl group or elimination derivatives thereof, carbonyl halide group, or an allenamide group, each of which may be optionally substituted. In some embodiments, the reactive substituent comprises a cycloalkene group, a cycloalkyne group, or an optionally substituted (hetero)cycloalkynyl group. In some embodiments, the anti-CD117 ADC comprises an anti-CD117 antibody conjugated to an amatoxin of formula I as disclosed herein, via a linker and a chemical moiety Z. In some embodiments, the linker includes a hydrazine, a disulfide, a thioether or a dipeptide. In some embodiments, the linker includes a dipeptide selected from Val-Ala and Val-Cit. In some embodiments, the linker includes a para-aminobenzyl group (PAB). In some embodiments, the linker includes the moiety PAB-Cit-Val. In some embodiments, the linker includes the moiety PAB-Ala-Val. In some embodiments, the linker includes a –((C=O)(CH2)n – unit, wherein n is an integer from 1-6. In some embodiments, the linker is –PAB-Cit-Val- ((C=O)(CH2)n –. In some embodiments, the linker includes a -(CH2)n – unit, where n is an integer from 2- 6. In some embodiments, the linker is –PAB-Cit-Val-((C=O)(CH2)n –. In some embodiments, the linker is –PAB-Ala-Val-((C=O)(CH2)n –. In some embodiments, the linker is -(CH2)n –. In some embodiments, the linker is -((CH2)n –, wherein n is 6. In some embodiments, the chemical moiety Z is
where S is a sulfur atom which represents the reactive substituent present within an antibody, or antigen-binding fragment thereof, that binds CD117 (e.g., from the -SH group of a cysteine residue). In some embodiments, an amatoxin as disclosed herein is conjugated to a linker- reactive moiety -L-Z′ having the following formula:
, where the wavy line indicates the point of attachment to a substituent on the cytotoxin (e.g., an amatoxin). This linker-reactive substituent group L-Z' may alternatively be referred to as N-beta- maleimidopropionyl-Val-Ala-para-aminobenzyl (BMP-Val-Ala-PAB). In some embodiments, an amatoxin as disclosed herein is conjugated to a linker- reactive moiety -L-Z′ having the following formula: , where the wavy line indicates the point of attachment to a substituent on the cytotoxin (e.g., an amatoxin). This linker-reactive substituent group L-Z' may alternatively be referred to as N-beta- maleimidopropyl-Val-Cit-para-aminobenzyl (BMP-Val-Cit-PAB). In some embodiments, the linker-reactive substituent group structure L-Z', prior to conjugation with the antibody or antigen binding fragment thereof, is: In some embodiments, the linker L and the chemical moiety Z, taken together as L-Z, is where S is a sulfur atom which represents the reactive substituent present within an antibody, or antigen-binding fragment thereof, such as an anti-CD117 antibody (e.g., from the - SH group of a cysteine residue). The wavy line at the linker terminus indicates the point of attachment to the amatoxin.
In some embodiments, the linker L and the chemical moiety Z, after conjugation to the antibody, taken together as L-Z-Ab, has the structure: where S is a sulfur atom which represents the reactive substituent present within an antibody, or antigen-binding fragment thereof, such as an anti-CD-117 antibody. The wavy line at the linker terminus indicates the point of attachment to the amatoxin. One of skill in the art will recognize the linker- reactive substituent group structure, prior to conjugation with the antibody or antigen binding fragment thereof, includes a maleimide as the group Z'. The foregoing linker moieties and amatoxin-linker conjugates, among others useful in conjunction with the compositions and methods described herein, are described, for example, in U.S. Patent Application Publication No.2015/0218220 and Patent Application Publication No. WO2017/149077, the disclosure of each of which is incorporated herein by reference in its entirety. Preparation of Antibody-Drug Conjugates In the ADCs as disclosed herein, an ant-CD117 antibody or antigen binding fragment thereof is conjugated to one or more cytotoxic drug moieties (D), e.g. about 1 to about 20 drug moieties per antibody, through a linker L and a chemical moiety Z as disclosed herein. The ADCs of the present disclosure may be prepared by several routes, employing organic chemistry reactions, conditions, and reagents known to those skilled in the art, including: (1) reaction of a reactive substituent of an antibody or antigen binding fragment thereof with a bivalent linker reagent to form Ab-Z-L as described herein above, followed by reaction with a drug moiety D; or (2) reaction of a reactive substituent of a drug moiety with a bivalent linker reagent to form D-L-Z, followed by reaction with a reactive substituent of an antibody or antigen binding fragment thereof as described herein above to form an ADC of formula D-L-Z-Ab, such as Am-Z-L-Ab. Additional methods for preparing ADC are described herein. In another aspect, the antibody or antigen binding fragment thereof has one or more lysine residues that can be chemically modified to introduce one or more sulfhydryl groups. The ADC is then formed by conjugation through the sulfhydryl group's sulfur atom as described herein above. The reagents that can be used to modify lysine include, but are not limited to, N- succinimidyl S-acetylthioacetate (SATA) and 2-Iminothiolane hydrochloride (Traut's Reagent).
In another aspect, the antibody or antigen binding fragment thereof can have one or more carbohydrate groups that can be chemically modified to have one or more sulfhydryl groups. The ADC is then formed by conjugation through the sulfhydryl group's sulfur atom as described herein above. In yet another aspect, the antibody can have one or more carbohydrate groups that can be oxidized to provide an aldehyde (-CHO) group (see, for e.g., Laguzza, et al., J. Med. Chem. 1989, 32(3), 548-55). The ADC is then formed by conjugation through the corresponding aldehyde as described herein above. Other protocols for the modification of proteins for the attachment or association of cytotoxins are described in Coligan et al., Current Protocols in Protein Science, vol.2, John Wiley & Sons (2002), incorporated herein by reference. Methods for the conjugation of linker-drug moieties to cell-targeted proteins such as antibodies, immunoglobulins or fragments thereof are found, for example, in U.S. Pat. No. 5,208,020; U.S. Pat. No.6,441,163; WO2005037992; WO2005081711; and WO2006/034488, all of which are hereby expressly incorporated by reference in their entirety. The foregoing linker moieties and amatoxin-linker conjugates, among others useful in conjunction with the compositions and methods described herein, are described, for example, in U.S. Patent Application Publication No.2015/0218220 and Patent Application Publication No. WO2017/149077, the disclosure of each of which is incorporated herein by reference in its entirety. The foregoing linker moieties and amatoxin-linker conjugates, among others useful in conjunction with the compositions and methods described herein, are described, for example, in U.S. Patent Application Publication No.2015/0218220 and Patent Application Publication No. WO2017/149077, the disclosure of each of which is incorporated herein by reference in its entirety. Examples In the following examples, the MGTA-117 antibody refers to Ab85 with an Fc region comprising D265C, L234A, L235A, and H435A mutations (i.e., the Ab85 comprising a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 9 and a light chain having an amino acid sequence as set forth in SEQ ID NO: 10 and conjugated to an amatoxin). Example 1. Use of Anti-CD117 ADC for Conditioning for HSC Transplantation
This example provides details of a study examining dose and time relationship between dosing of MGTA-117 and the resulting depletion of bone marrow stem cells and peripheral reticulocytes utilizing a non-human primate (NHP) model. Hematopoietic stem cell transplant (HSCT) is a highly effective and potentially curative treatment for malignant and non-malignant blood disorders. However, current conditioning regimens which are non-selective and used with toxic multi-dosing regimens limit the use of HSCT due to regimen-related mortality and morbidities including organ toxicity, infertility, and secondary malignancies. To address these issues, a potent, targeted antibody-drug conjugate (ADC) targeting CD117 (c-kit) conjugated using a stable linker to an amanitin payload has been developed (i.e., MGTA-117). Upon binding to CD117, MGTA-117 is rapidly internalized and, following the lysosomal degradation and subsequent release of the amanitin payload intracellularly, inhibits RNA polymerase 2 leading to apoptosis of quiescent and cycling cells (data not shown). In addition, the antibody component of the ADC was engineered for rapid clearance and is an antagonist of Stem Cell Factor (SCF), the natural ligand for CD117, providing a dual mechanism of target cell depletion. MGTA-117 is highly effective at killing human CD117+ stem cells and erythroid precursors in vitro and in vivo in humanized NSG mice. In NHPs, a single administration of MGTA-117 resulted in significant depletion of stem and progenitor cells in the bone marrow and peripheral blood reticulocytes reflecting the depletion of erythroid precursors. The data presented are pooled across several individual studies with MGTA-117 in cynomolgus NHPs. MGTA-117 was dosed at 0.05 to 3 mg/kg via intravenous infusion over 60 minutes in NHPs to determine the time course of pharmacokinetic (PK) and pharmacodynamic (PD) conditioning responses within stem cell and blood populations. Tissue sample collection (i.e., peripheral blood or bone marrow aspirate) occurred prior to the single IV dose and on days 4, 7, 14, 21, and/or 28 days post dose. Standard hematology measurements were also collected to evaluate non-targeted responses to MGTA-117 administration. Flow cytometry analysis was performed on peripheral blood and bone marrow aspirate samples. For analysis of stem cells counts, single cells in a heterogeneous mixture were detected, counted, sorted, and profiled via single-file cell passage through flow cytometry. Cell composition was assessed using fluorescently conjugated antibodies against specific cell surface markers. Fluorescently conjugated antibodies are excited by a laser to emit light at specific wavelengths. Fluorescent emission is measured by an electronic detection apparatus as light scatter and fluorescence intensity. Specific cell populations within the heterogenous mixture were identified and quantified based on their emission profile. For estimation of
reticulocytes counts, standard hematology samples were collected and analyzed at the in-life testing facilities. For PK analysis, an enzyme-linked immunosorbent assay (ELISA)-based assay was utilized for the estimation of ADC and therapeutic antibodies within each individual study. PK data presented reflect the mean (±SD) ADC concentrations collected within each animal receiving MGTA-117 after pooling the data at each relevant dose. The lower limit of quantification for MGTA-117 was consistent across each study. Intravenous administration of MGTA-117 resulted in dose-dependent increases in exposures, with rapid rates of clearance at all dose levels. Nonlinear rates of clearance were apparent at the higher doses of MGTA-117, consistent with the expected target-mediated drug distribution profile, where nonlinear clearance is attributed to saturation of CD117 binding and internalization of the ADC. Even at the highest doses tested, MGTA-117 was cleared quickly and was below the limit of quantification in blood 10 days post dose (Fig.1). Within NHPs, greater than 90% depletion of CD34+/CD90+/45RA- stem cells within bone marrow were observed at doses of 0.3 mg/kg and higher (Fig.3A-B). Lasting stem cell depletion was observed well after clearance of MGTA-117 from blood; the onset of stem cell depletion occurred as early as 7 days post dose with recovery delayed until at least 21 days post dose (Fig.3A-3B). Because myeloid progenitors also express CD117+, blood reticulocytes were assessed as an indirect surrogate for the depletive effects of MGTA-117 in the bone marrow. At all doses tested, depletion of blood reticulocyte populations was observed (Fig.2). Fig.2 shows that robust depletion of blood reticulocyte counts were also observed, an indirect surrogate for the depletive effects of MGTA-117 on progenitors in the bone marrow. While the onset of reticulocyte depletion is similar to stem cell populations, the relative recovery appears to correlate directly with the clearance of MGTA-117 below active concentrations. Blood neutrophils and platelets were largely unaffected by any dose of MGTA-117 on day 7 (data not shown), confirming the targeted effects on CD117+ expressing cell populations. MGTA-117 was well-behaved with consistent PK-PD across a wide range of doses within NHPs. MGTA-117 demonstrated rapid clearance from blood. The observed dose- dependent changes in clearance are consistent with saturation of receptor binding and internalization. At doses of 0.3 mg/kg and higher, the observed PD responses confirm targeted depletion of CD117-expressing populations, with lasting stem cell responses beyond the actual clearance of ADC. At all doses tested, depletion of blood reticulocyte populations were observed, with the relative recovery correlated directly with the clearance of MGTA-117. The significant and rapid reticulocyte depletion supported the hypothesis that reticulocytes may be a
biomarker for bone marrow depletion. The dose dependency of PD responses suggests that effective doses of MGTA-117 appear to require maintenance of receptor occupancy to confer the targeted cytotoxic effects via intracellular delivery of amanitin. Mechanistic modeling of this predictable and potent profile in NHPs is supportive of predictions of biologic activity at low doses in humans. Overall, the rapid PK clearance and prolonged stem cell depletive responses provide an ideal profile that supports MGTA-117 for clinical development as conditioning agent prior to transplant. Example 2. Use of Anti-CD117 ADC for CD117+ Depletion in Human Patients This example provides details of a clinical study designed to selectively deplete CD117 positive (CD117+) cells from human patients with adult acute myeloid leukemia (AML) and myelodysplasia-excess blasts (MDS-EB). A multicenter, open-label, study was initiated to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), blast depletion activity, and potential anti- leukemic activity of MGTA-117 and to establish the minimum safe and biologically-effective dose of a single dose of MGTA-117 (administered intravenously) in relapsed or refractory CD117+ acute myeloid leukemia (R/R CD117+ AML) patients and patients with MDS-EB. The study also will evaluate anti-drug antibodies (ADA). The study consists of escalating single-dose cohorts using a standard 3+3 design. MGTA-117 is an anti-CD117 ADC comprising antibody Ab85 (human IgG1) and an amanitin with a non-cleavable linker. Subjects were treated with a single dose of MGTA-117 prepared and administered by IV infusion over a 1-hour period. The primary objectives of the study included (i) characterization of the safety and tolerability of MGTA-117 in participants; (ii) characterization of the PK profile of MGTA-117 in relapsed/refractory AML (R/R AML) and MDS-EB participants; and (iii) establishment of a minimum safe and biologically effective dose of MGTA-117 in participants. The flowing primary outcomes were chosen for assessment: 1. Incidence rate of treatment emergent adverse events (TEAEs) leading to study drug discontinuation [ Time Frame: 21 days ] 2. Incidence rate of treatment emergent >= Grade 3 clinical laboratory abnormalities as assessed by CTCAE v5.0 [ Time Frame: 21 days ]
3. Assess the clinically significant changes from baseline in vital signs, ECGs and laboratory parameters [ Time Frame: 21 days ] 4. Pharmacokinetics profile of MGTA-117 [ Time Frame: 21 days ]; Investigate area under the curve (AUC) 5. Pharmacokinetics profile of MGTA-117 Time Frame: 21 days ]; Investigate maximum plasma concentration (Cmax) 6. Pharmacokinetics profile of MGTA-117 [ Time Frame: 21 days ]; Investigate time of maximum concentration (Tmax) 7. Pharmacokinetics profile of MGTA-117 [ Time Frame: 21 days ] Investigate the half-life (t1/2) 8. Pharmacokinetics profile of MGTA-117 [ Time Frame: 21 days ] Investigate the plasma concentration 9. To establish a minimum safe and biologically effective dose [ Time Frame: 7 days ] Assess the CD117 receptor occupancy in circulating leukemic blasts 10. To establish a minimum safe and biologically effective dose [ Time Frame: 21 days ] Objectives of the study include (i) assessing the PD of MGTA-117 in participants; (ii) characterizing the immunogenicity of MGTA-117 in participants; and (iii) assessing the preliminary anti-leukemic activity of MGTA-117 and changes in HSCs. Patients chosen for the study were 18-75 years of age, inclusive, and had the following inclusion criteria: 1. Participant must have a World Health Organization (WHO)-defined diagnosis of R/R AML and meet one of the following criteria: - The participant has experienced primary AML induction failure or R/R AML OR - The participant has a WHO-defined diagnosis of MDS-EB and has failed/is refractory to HMA OR - Presence of MRD in morphologic CR 2. CD117+ based on IHC or flow cytometry 3. Participant must have an identified HSC donor (related donor or unrelated donor), haplo- identical transplant donor, or umbilical blood donor. 4. Participant's Eastern Cooperative Oncology Group (ECOG) performance status must be ≤2.
5. Participant must have adequate baseline hepatic function. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤2 x upper limit of normal (ULN), and serum bilirubin ≤1.5 x ULN. 6. Estimated creatinine clearance ≥60 mL/min 7. Adequate cardiac function as demonstrated by cardiac left ventricular ejection fraction ≥40% or perform New York Heart Association (NYHA) classification I and II Exclusion criteria to participate in the study included the following: 1. Acute promyelocytic leukemia (APL). 2. Known active central nervous system (CNS) leukemia or chloroma (granulocyte sarcoma). 3. Received HSCT within 6 months prior to dosing 4. Received chimeric antigen-receptor cell therapies within 6 months prior to dosing 5. Has active graft-versus-host disease (GVHD). 6. Active hepatitis B (Hep-B) or hepatitis C (Hep-C) infection or history of human immunodeficiency virus (HIV). 7. Participant with a QTc value >470 msec 8. Participant has received another investigational drug or device within 14 days or 5 half- lives of dosing, whichever is longer. 9. Participant has any clinically significant medical condition, which in the opinion of the Investigator may place the participant at an unacceptable risk. 10. Active uncontrolled systemic bacterial, fungal, or viral infection 11. Participant has a history of serious allergic reactions, which in the opinion of the Investigator may pose an increased risk of serious infusion reactions. 12. Participant has had any systemic antileukemia treatment within 14 days except hydroxyurea, which is permitted until 24 hours prior to MGTA-117 dosing. 13. Participant has received prior anti-CD117 antibody treatment. 14. Participant has received gemtuzumab ozogamicin (Mylotarg) within the last 3 months prior to dosing. 15. Participant has received recent monoclonal antibody as anti-leukemic therapy within the last 30 days or 5 half-lives, whichever is longer.
16. Participant has received recent vaccination within the last 14 days prior to dosing. 17. Participant has Grade 2 or higher electrolyte abnormality at screening The study was designed for 8 cohorts with dose escalation. Example 3. Results from the First-in-Human Clinical Trial for MGTA-117 (Anti-CD117 ADC) This example provides initial results for cohorts 1-3 from the clinical trial described in Example 2. Baseline demographics are provided in Table 5. The R/R AML study population had a poor prognosis with a high burden of disease despite multiple previous lines of therapy. Key Inclusion / Exclusion Criteria • CD117+ R/R AML or MDS-EB • Age 18-75 with identified HSCT donor • ECOG performance status ≤2 • No significant organ dysfunction • No systemic infections • No APL, active CNS leukemia or chloroma • Washouts for prior anti-leukemic therapies Dosing is described below for each cohort in Table 4. Table 4
Table 5: Baseline Participant Demographics and Disease Characteristics (Cohorts 1-3)
Between all three cohorts, 15 participants were enrolled and treated (see Table 5). Across all participants, 4 were enrolled in Cohort 1, 6 were enrolled in Cohort 2, and 5 were enrolled in Cohort 3. Of the 4 participants in cohort 1, 3 completed the study observation period and 1 discontinued. Of the 6 participants in Cohort 2, 3 completed the study observation period and 3 discontinued. All 5 participants in cohort 3 completed the observation period. All 4 participant discontinuations were determined to be unrelated to MGTA-117. Safety results from cohorts 1 and 2 suggested MGTA-117 is well tolerated at low doses. Treatment-emergent AEs (TEAE) were generally consistent with the underlying disease and associated complications. There were no unexpected AEs, TEAEs, treatment-related deaths, treatment-related infusion reactions, or dose-limiting toxicities observed. The observed treatment-related AEs were expected, transient, low-grade, and resolved without any intervention. There were no treatment-related infusion reactions observed. Importantly, no MGTA-117-related TEAEs led to study discontinuation. Regardless of causality, disease progression occurred in 20% of participants, liver enzyme elevation occurred in 20% of participants, nausea occurred in 27% of participants, headache occurred in 20%, constipation occurred in 27% of participants, hypokalaemia occurred in 27% of participants, hypomagnesaemia occurred in 20% of participants, and leukopenia occurred in 20% of participants. Two participants (marked with 2 and 3) presented with severe neutropenia and Grade 2 or 3 leukopenia at baseline. An overview of the safety results across both cohorts is presented in Table 6. Table 6: Safety Data from Cohorts 1-3
To assess the PK of MGTA-117 in human subjects, MGTA-117 concentrations were measured at 0, 0.25, 2, 4, 8, 24, 36, and 48 hours following the infusion. Maximum concentrations of MGTA-117 were reached within 1 hour of the infusion. MGTA-117 was rapidly cleared, with a T1/2 of 10 hours or less. No measurable MGTA-117 was detected at 48 hours following the infusion across all three doses tested (Fig.4). Further, free amanitin-containing payload was undetectable in blood across all participants. MGTA-117 rapidly bound CD117+ blast cells in blood, as measured by a receptor occupancy assay. The percent of receptor occupancy (RO) in blast cells was measured at 0, 0.25, 2, 4, 8, 24, and 48 hours following the infusion of MGTA-117 as described in Fig.5. Binding of CD117+ cells was observed in all participants at 15-minute initial measurement after dosing. RO decline was observed in all dosed participants indicating internalization of MGTA- 117. Higher receptor occupancy was observed in Cohorts 2 and 3 relative to Cohort 1. Longer duration of receptor occupancy was observed in Cohorts 2 and 3 relative to Cohort 1. The ability for MGTA-117 to deplete CD117+ blast cells was measured in blood samples. This depletion is described in Fig.6 for Cohorts 1-3. CD117+ blast cell depletion was observed in the blood in Cohorts 2 and 3. Higher depletion in Cohorts 2 and 3 compared to Cohort 1 observed, consistent with higher and longer receptor occupancy in the blood.
MGTA-117 was also able to deplete CD117+ red blood cell (RBC) progenitors in bone marrow. Samples obtained during screening and following MGTA-117 infusion were analyzed via flow cytometry. Participant 3 from Cohort 1 exhibited a significant, depletion of CD117+ RBC progenitors in bone marrow (Fig.7). MGTA-117 was further shown to deplete blast cells in bone marrow. These results are described in Fig.8. Greater depletion was observed in the bone marrow of more Cohort 3 participants compared to previous cohorts. MGTA-117 depleted blasts in blood AND bone marrow in 3 participants (#11, 13, 14) in Cohort 3. Two relapsed/refractory participants achieved complete remission (CR), specifically one participant with AML participant (Cohort 1), one participant with MDS (Cohort 3). Both participants had similar clinical morphology to transplant-eligible patients at baseline due to low blast counts in the blood and bone marrow. anti-leukemic Based on the results from early-stage cohorts, MGTA-117 has demonstrated potential as a safe, well-tolerated, and efficacious therapeutic for depleting CD117+ cells in patients prior to HSCT (i.e., as a conditioning agent). A first case study is presented for participant 2 in cohort 1. Said participant, a 58-year- old male, was initially diagnosed with FLT3 mutation-positive AML, presenting with 37% bone marrow blasts. Following an initial treatment regimen of CLIA (Cladribine, AraC, and Idarubicin), he entered partial remission with 18% bone marrow blasts. He underwent a second round of treatment, receiving FLAG-IDA (Fludarabine, cytarabine, Granulocyte-Colony stimulating factor, and idarubicin) with persistent bone marrow blast cells. At the time of screening for the study, he had 6% bone marrow blast cells.14 days after treatment with MGTA-117 at 0.02 mg/kg, he entered complete remission and was minimal residual disease (MRD) positive with 1% bone marrow blasts. He received a myeloablative MAC regimen (Venetoclax, Thiotepa, Busulfan, Fludarabine, and Cladribine) prior to receiving a successful allogeneic HSCT. He was placed on 3 cycles of azacytidine and venetoclax as a maintenance anti-leukemic therapy and cytotaxan, tacrolimus, and mycophenylate mofetil as a graft vs host disease prophylaxis. An overview of this patient and their case study is shown in Fig.9. MGTA-117 has further demonstrated potential as a conditioning regimen for a patient diagnosed with MDS prior to HSCT. A second case study is presented for participant 14 in cohort 3. Said participant, a 73-year-old female, was initially diagnosed with ASXL1, BCOR, U2AF1 mutation positive, treatment refractory MDS. She presented with 17% bone marrow blasts at the time of diagnosis. She received decitabine treatment for 1 year. At the time of
screening for the study, she presented with 10% bone marrow blasts.7 days after treatment with MGTA-117 at 0.08 mg/kg, she entered complete remission and was MRD positive with 3% bone marrow blasts, rendering her transplant eligible. An overview of this patient’s case study is shown in Fig.10. Other Embodiments All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference. While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the invention that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. Other embodiments are within the claims.
Claims
CLAIMS What is claimed is: 1. A method of depleting a population of CD117+ cells in a human patient in need thereof, wherein the method comprises administering to the patient a dose of from about 0.02 to about 3.0 mg/kg of an anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, and wherein the antibody comprises a heavy chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 3, 4, and 5, respectively, and comprises a light chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 6, 7, and 8, respectively, such that the population of CD117+ cells in the human patient in need thereof, is depleted.
2. A method of conditioning a human patient for an hematopoietic stem cell (HSC) transplant comprising administering a dose of from about 0.02 to about 3.0 mg/kg of an anti- CD117 antibody drug conjugate (ADC) to the human patient, wherein the ADC comprises an anti-CD117 antibody conjugated to an amatoxin via a linker, and wherein the anti-CD117 antibody comprises a heavy chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 3, 4, and 5, respectively, and comprises a light chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 6, 7, and 8, respectively, such that the human patient is conditioned for an HSC transplant.
3. An anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti- CD117 antibody conjugated to an amatoxin via a linker, and wherein the antibody comprises a heavy chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 3, 4, and 5, respectively, and comprises a light chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 6, 7, and 8, respectively, for use in depleting a population of CD117+ cells in a human patient in need thereof, wherein the ADC is administered to the patient in a dosage of from about 0.02 to about 3.0 mg/kg.
4. An anti-CD117 antibody drug conjugate (ADC), wherein the ADC comprises an anti- CD117 antibody conjugated to an amatoxin via a linker, and wherein the antibody comprises a heavy chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 3, 4, and 5, respectively, and comprises a light chain variable region comprising a CDR1, CDR2 and CDR3 having an amino acid sequence as set forth as SEQ ID NO: 6, 7, and 8, respectively, for use in conditioning a human patient for an hematopoietic stem cell (HSC) transplant, wherein the ADC is administered to the patient in a dosage of from about 0.02 to about 3.0 mg/kg.
5. The method or use of any one of claims 1 to 4, wherein the dosage is selected from the group consisting of about 0.02, 0.04, 0.076, 0.08.0.127, 0.13, 0.15, 0.19, 0.247, 0.30, 0.309, 0.386, 0.483, 0.603, 0.754, 0.942, 1.0, and 3.0 mg/kg.
6. The method or use of any one of claims 1 to 4, wherein the dosage is selected from the group consisting of 0.02, 0.04, 0.076, 0.08.0.127, 0.13, 0.15, 0.19, 0.247, 0.30, 0.309, 0.386, 0.483, 0.603, 0.754, 0.942, 1.0, and 3.0 mg/kg.
7. The method of use of any one of claims 1-6, wherein the anti-CD117 antibody comprises a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 2.
8. The method or use of any one of claims 1-6, wherein the antibody comprises a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 9 and a light chain having an amino acid sequence as set forth in SEQ ID NO: 10.
9. The method or use of any one of claims 1-8, wherein the anti-CD117 antibody comprises an Fc region comprising a D265C mutation (according to EU index).
10. The method or use of any one of claims 1-8, wherein the anti-CD117 antibody comprises an Fc region comprising a L234A mutation and a L235A mutation (according to EU index).
11. The method or use of any one of claims 1-8, wherein the anti-CD117 antibody comprises an Fc region comprising a H435A mutation (according to EU index).
12. The method or use of any one of claims 1-11, wherein the ADC has the structure of formula (I):
(Formula I), or a stereoisomer thereof; wherein: Q is S; Ab is the anti-CD117 antibody; and S L-Z i
s , wherein represents the point of attachment to the antibody (Ab) and represents the point of attachment to the amatoxin. 13. The method or use of claim 12, wherein the anti-CD117 ADC has a structure according to Formula Ia:
(Formula Ia) 14. The method or use of any one of claims 1-11, wherein the ADC has the structure of formula (III): (III), or a stereoisomer thereof; wherein: X is S or S(O); L is a linker;
Z is a chemical moiety formed by a coupling reaction between a reactive substituent Z' present on L and a reactive substituent present within the anti-CD117 antibody; and Ab is the anti-CD117 antibody.
15. The method or use of any one of claims 1-11, wherein the ADC has the structure of formula (IV): (IV), wherein Ab is the anti-CD117 antibody.
16. The method or use of any one of claims 1-15, further comprising administering a cell transplantation to the human patient.
17. The method or use of claim 16, wherein the cell transplantation comprises a population of stem cells.
18. The method or use of claim 17, wherein the stem cells are allogeneic.
19. The method or use of claim 18, wherein the human patient has a cancer.
20. The method or use of claim 19, wherein the cancer is a leukemia.
21. The method or use of claim 20, wherein the leukemia is relapsed or refractory acute myeloid leukemia.
22. The method or use of claim 17, wherein the human patient has myelodysplasia, e.g., myelodysplasia with excess blasts (MDS-EB).
23. The method or use of claim 16, wherein the cell transplantation comprises genetically modified cells.
24. The method or use of claim 23, wherein the human patient has a hemoglobinapthy or a lysosomal disorder.
25. The method or use of any one of claims 1-24, wherein the human patient is administered a single dose of the anti-CD117 ADC.
26. The method or use of any one of claims 1-25, wherein the anti-CD117 ADC is administered to the human patient intravenously.
27. The method or use of any one of claims 1-26, wherein the patient is administered a second dose of the anti-CD117 ADC upon achieving a partial remission.
28. The method or use of any one of claims 1-27, wherein the human subject has at least one of the following characteristics: is an adult who is age 18-75 inclusive; has an identified HSCT donor prior to administration of the anti-CD117 ADC; and has an Eastern Cooperative Oncology Group (ECOG) performance status of <2; has no significant organ dysfunction prior to administration of the anti-CD117 ADC; has no systemic infections prior to administration of the anti-CD117 ADC; has no APL, active CNS leukemia or chloroma prior to administration of the anti-CD117 ADC; or has had washouts for prior anti-leukemic therapies prior to administration of the anti- CD117 ADC.
29. The method or use of any one of claims 1-28, wherein the human subject does not have at least one of the following characteristics prior to administration of the anti-CD117 ADC: acute promyelocytic leukemia (APL); active central nervous system (CNS) leukemia; chloroma (granulocyte sarcoma); received an HSC transplant within 6 months of being selected for treatment; active graft-versus-host disease (GVHD); active hepatitis B (Hep-B) or hepatitis C (Hep-C) infection; a history of human immunodeficiency virus (HIV); a QTc value >470 msec; has received another investigational drug or device within 30 days; active uncontrolled systemic bacterial, fungal, or viral infection; any systemic antileukemia treatment within 14 days except hydroxyurea; received prior ADC treatment or anti-CD117 antibody treatment; received recent monoclonal antibody therapy within the last 30 days; received recent vaccination within the last 14 days; or Grade 2 or higher electrolyte abnormality at screening.
30. A method of depleting CD117+ cells in a human subject having a hematological cancer, the method comprising administering an anti-CD117 antibody drug conjugate (ADC) to the human subject having a hematological cancer, thereby depleting CD117+ cells in the subject, wherein the anti-CD117 ADC comprises an anti-CD117 antibody (Ab) conjugated via a linker (L) to an amatoxin (Am), wherein the anti-CD117 ADC has a structure selected from the group consisting of Formula I:
Formula I), or a stereoisomer thereof; wherein: Q is S; Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:7, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 8; S L-Z comprises a non-cleavable linker , wherein represents the point of attachment to the antibody (Ab) and represents the point of attachment to the amatoxin; formula (III):
(III), or a stereoisomer thereof; wherein: X is S or S(O); L is a linker; Z is a chemical moiety formed by a coupling reaction between a reactive substituent Z' present on L and a reactive substituent present within the anti-CD117 antibody; and Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:7, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 8; and formula (IV):
(IV), wherein Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:7, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 8.
31. An antibody drug conjugate (ADC) comprising an anti-CD117 antibody (Ab) conjugated via a linker (L) to an amatoxin (Am) for use in depleting CD117+ cells in a human subject having a hematological cancer, wherein the anti-CD117 ADC has a structure selected from the group consisting of Formula I:
(Formula I), or a stereoisomer thereof; wherein: Q is S; Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:7, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 8; S L-Z is , wherein represents the point of attachment to the antibody (Ab) and represents the point of attachment to the amatoxin; formula (III):
(III), or a stereoisomer thereof; wherein: X is S or S(O); L is a linker; Z is a chemical moiety formed by a coupling reaction between a reactive substituent Z' present on L and a reactive substituent present within the anti-CD117 antibody; and Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:7, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 8; and formula (IV):
(IV), wherein Ab is an anti-CD117 antibody comprising a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:4, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 5; and comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:7, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO: 8.
32. The method or use of claims 30-31, wherein the hematologic cancer is Acute Myeloid Leukemia (AML) or Myelodysplasia-Excess Blasts (MDS-EB).
33. The method or use of claim 32, wherein the AML is CD117+ AML.
34. The method or use of any one of claims 30-33, wherein the human subject has relapsed or refractory AML (R/R AML).
35. The method or use of any one of claims 30-34, wherein the human subject has at least one of the following characteristics: is an adult who is age 18-75 inclusive; has an identified HSCT donor prior to administration of the anti-CD117 ADC; and has an Eastern Cooperative Oncology Group (ECOG) performance status of <2;
has no significant organ dysfunction prior to administration of the anti-CD117 ADC; has no systemic infections prior to administration of the anti-CD117 ADC; has no APL, active CNS leukemia or chloroma prior to administration of the anti-CD117 ADC; or has had washouts for prior anti-leukemic therapies prior to administration of the anti- CD117 ADC.
36. The method or use of any one of claims 30-35, wherein the human subject does not have at least one of the following characteristics prior to administration of the anti-CD117 ADC: acute promyelocytic leukemia (APL); active central nervous system (CNS) leukemia; chloroma (granulocyte sarcoma); received an HSC transplant within 6 months of being selected for treatment; active graft-versus-host disease (GVHD); active hepatitis B (Hep-B) or hepatitis C (Hep-C) infection; a history of human immunodeficiency virus (HIV); a QTc value >470 msec; has received another investigational drug or device within 30 days; active uncontrolled systemic bacterial, fungal, or viral infection; any systemic antileukemia treatment within 14 days except hydroxyurea; received prior ADC treatment or anti-CD117 antibody treatment; received recent monoclonal antibody therapy within the last 30 days; received recent vaccination within the last 14 days; or Grade 2 or higher electrolyte abnormality at screening.
37. The method or use of any one of claims 30-36, wherein the anti-CD117 ADC is administered to the human subject as a single dose.
38. The method or use of any one of claims 30-37, wherein the anti-CD117 antibody comprises a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 1, and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 2.
39. The method or use of any one of claims 30-38, wherein the anti-CD117 antibody comprises an Fc region comprising amino acid substitutions L234A, L235A, D265C and H435A.
40. The method or use of any one of claims 30-39, wherein the anti-CD117 antibody comprises a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 9 and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 10.
41. The method or use of any one of claims 30-40, wherein the anti-CD117 ADC has a structure according to Formula Ia: (Formula Ia)
42. The method or use of any one of claims 30-41, wherein the anti-CD117 ADC is administered to the human subject at a dose of about 0.02 mg/kg.
43. The method or use of any one of claims 30-41, wherein the anti-CD117 ADC is administered to the human subject at a dose of about 0.04 mg/kg.
44. The method of any one of any one of claims 30-41, wherein the anti-CD117 ADC is administered to the human subject at a dose of about 0.08 mg/kg.
45. The method or use of any one of claims 30-41, wherein the anti-CD117 ADC is administered to the human subject at a dose of about 0.076 mg/kg.
46. The method or use of any one of claims 30-41, wherein the anti-CD117 ADC is administered to the human subject at a dose of about 0.13 mg/kg.
47. The method or use of any one of claims 30-41, wherein the anti-CD117 ADC is administered to the human subject at a dose of about 0.19 mg/kg.
48. The method or use of any one of claims 30-47, wherein the human subject is administered a single dose of the anti-CD117 ADC.
49. The method or use of any one of claims 30-48, wherein the anti-CD117 ADC is administered to the human subject intravenously.
50. The method or use of any one of claims 30-49, wherein the human subject achieves complete remission of MDS or the hematological cancer.
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