WO2014058947A1 - Compositions et méthodes destinées à traiter le cancer à l'aide d'un inhibiteur de pi3k et d'un immunoconjugué maytansinoïde anti-cd19 - Google Patents

Compositions et méthodes destinées à traiter le cancer à l'aide d'un inhibiteur de pi3k et d'un immunoconjugué maytansinoïde anti-cd19 Download PDF

Info

Publication number
WO2014058947A1
WO2014058947A1 PCT/US2013/063983 US2013063983W WO2014058947A1 WO 2014058947 A1 WO2014058947 A1 WO 2014058947A1 US 2013063983 W US2013063983 W US 2013063983W WO 2014058947 A1 WO2014058947 A1 WO 2014058947A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
immunoconjugate
ser
cancer
pharmaceutically acceptable
Prior art date
Application number
PCT/US2013/063983
Other languages
English (en)
Inventor
Ti Cai
Tal ZAKS
Angela Romanelli
Original Assignee
Sanofi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi filed Critical Sanofi
Publication of WO2014058947A1 publication Critical patent/WO2014058947A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • 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
    • A61K47/6801—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
    • 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
    • A61K47/6871—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 an enzyme
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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

Definitions

  • an anti-CD 19 maytansinoid immunoconjugate and a phosphoinositide 3-kinase (PI3K) inhibitor which are therapeutically useful in the treatment of cancer.
  • compositions and uses thereof in the treatment of a variety of cancers are provided herein.
  • the immunoconjugate comprising a light chain and a heavy chain, said light chain having the sequence represented in SEQ ID NO. 7, and said heavy chain having the sequence represented in SEQ ID NO. 8.
  • the immunoconjugate further comprises a cytotoxic agent that is a maytansinoid such as DM4 that is covalently attached, directly or via a cleavable or non-cleavable linker, to the antibody wherein about 3.5 molecules of maytansinoid are bound through the SPDB linker to each antibody molecule.
  • a cytotoxic agent that is a maytansinoid such as DM4 that is covalently attached, directly or via a cleavable or non-cleavable linker, to the antibody wherein about 3.5 molecules of maytansinoid are bound through the SPDB linker to each antibody molecule.
  • methods of treating a subject with cancer comprise administering to the subject a therapeutically effective amount of Compound (1), or a pharmaceutically acceptable salt thereof, in combination with Immunoconjugate (1).
  • the method of treating a subject with cancer comprises administering to the subject a first dosage of a PI3K inhibitor, and a second dosage of an anti- CD 19 maytansinoid immunoconjugate wherein said PI3K inhibitor is Compound (1).
  • the method of treating a subject with cancer comprises administering to the subject a first dosage of an anti-CD 19 maytansinoid immunoconjugate, and a second dosage of a PI3K inhibitor wherein said PI3K inhibitor is Compound (1).
  • the methods involve treating cancer selected from the group consisting of lymphomas and leukemias including, but not limited to, germinal center B-cell like diffuse large B-cell lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia and mantle cell lymphoma.
  • lymphomas and leukemias including, but not limited to, germinal center B-cell like diffuse large B-cell lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia and mantle cell lymphoma.
  • compositions and methods of use described herein are in amounts (i.e., either in the composition are in an administered dosage) that provide a synergistic effect in the treatment of the subject.
  • a combination for use in treating a patient with cancer comprising a therapeutically effective amount of (A) Compound (1), or a pharmaceutically acceptable salt thereof, and (B) Immunoconjugate (1).
  • uses of a combination comprising a therapeutically effective amount of (A) Compound (1), or a pharmaceutically acceptable salt thereof, and (B) Immunoconjugate (1) are provided for the preparation of a medicament for use in treatment of lymphoma.
  • kits comprising: (A) Compound (1), or a
  • Figure 1 is a schematic showing the structure of an anti-CD 19 maytansinoid immunoconjugate.
  • Figure 2 demonstrates the enhanced apoptosis observed with Compound (1) (i.e. CPD(l)) and an anti-CD19 maytansinoid immunoconjugate (i.e. IC(1)) in the OCI-LY7 cell line.
  • Compound (1) i.e. CPD(l)
  • an anti-CD19 maytansinoid immunoconjugate i.e. IC(1)
  • Figure 3 demonstrates the enhanced anti-proliferative activity observed with
  • Compound (1) i.e. CPD(l)
  • an anti-CD19 maytansinoid immunoconjugate i.e. IC(1)
  • compositions and methods for the treatment of cancer are provided.
  • compositions and methods comprise inhibitors of the phosphoinositide 3-kinase (PI3K) pathway (Compound (1)) and an anti-CD 19 maytansinoid immunoconjugate
  • Immunoconjugate (1) Compound (1) and Immunoconjugate (1) can be administered in a single dosage form, or separate dosage forms.
  • Compound (1) 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one, is a selective inhibitor of class I PI3K lipid kinases.
  • Compound (1) targets both PI3K isoforms (IC 50 values in nM: PI3Ka 39, ⁇ 3 ⁇ 113, ⁇ 3 ⁇ 43, ⁇ 3 ⁇ 9) and mTOR (157 nM).
  • Compound (1) alone inhibits tumor growth in mice bearing xenografts in which PI3K signaling is activated, such as the PTEN-deficient PC-3 prostate adenocarcinoma, U87-MG gliobastoma, A2058 melanoma and WM -266-4 melanoma, or the PIK3CA mutated MCF7 mammary carcinoma.
  • Compound (1) is the subject of several clinical trials involving patients with, for example, solid tumors, lymphoma, glioblastoma or hormone receptor-positive breast cancer.
  • CD 19 is the earliest differentiation antigen of the B lymphocyte lineage, expressed on most B-cells, but not detected on plasma cells, stem cells, or on normal myeloid lineage. Therefore, CD 19 is expressed on tumor cells from all B cell-derived neoplasms (B-cell non- Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia), except myeloma.
  • Immunoconjugate (1) is an antibody-drug conjugate composed of a humanized IgGl monoclonal antibody, huB4 (Roguska et al, Proc. Natl. Acad. Sci. USA, 91: 969-973, 1994), which specifically targets the CD 19 antigen, conjugated through a disulfide link to the maytansinoid derivative DM4, a potent tubulin inhibitor (US 2004/0235840).
  • the structure of Immunoconjugate (1) is disclosed in Figure 1. After binding to the CD 19 antigen,
  • Immunoconjugate (1) undergoes internalization and intracellular release of DM4.
  • the entire contents of Roguska et al, Proc. Natl. Acad. Sci. USA, 91: 969-973, 1994 are incorporated herein by reference.
  • methods for treating subjects with cancer comprise administering to the subject a therapeutically effective amount of an anti-CD 19 maytansinoid immunoconjugate referred to herein as
  • Immuno conjugate (1) and a therapeutically effective amount of a PI3K inhibitor having the structural Formula (1), as further described below.
  • Immunoconjugate (1) and Compound (1) can be in single or separate dosage forms.
  • inventive methods and compositions comprise a PI3K inhibitor having the following s
  • Compound (1) 2-amino-8-ethyl-4-methyl-6-(lH-pyrazol-5- yl)pyrido[2,3-d]pyrimidin-7(8H)-one.
  • the preparation and properties of Compound (1) are provided in, for example, International
  • Patent Publication No. WO 07/044813 particularly Example 56 therein.
  • the entire contents of WO 07/044813 are incorporated herein by reference.
  • Neutral and salt forms of the compound of Formula (1) are all considered herein.
  • the anti-CD 19 maytansinoid immunoconjugate (Immunoconjugate (1)) comprises two primary components, a cell-binding agent and a cytotoxic agent.
  • cell binding agent refers to an agent that specifically recognizes and binds the CD 19 antigen on the cell surface.
  • the cell-binding agent is an antibody which binds specifically to the CD 19 antigen.
  • the said antibody comprises six complementary determining region (CDR), said CDR having the sequences represented in SEQ ID NOs 1 to 6.
  • the antibody comprises a light chain, wherein the sequence of the said light chain has at least 60%, at least 75%, at least 85%, at least 90 %, at least 95 % or at least 99% identity with the sequence displayed in SEQ ID NO. 7.
  • the antibody comprises a heavy chain, wherein the sequence of the said heavy chain has at least 60%, at least 75%, at least 85%, at least 90 %, at least 95 % or at least 99% identity with the sequence displayed in SEQ ID NO. 8.
  • the antibody of the invention is the humanized antibody huB4 described in Roguska et al. (Proc. Natl. Acad. Sci. USA, 91 : 969-973, 1994).
  • the antibody huB4 according to the invention comprises a light chain and a heavy chain, said light chain having the sequence represented in SEQ ID NO. 7, and said heavy chain having the sequence represented in SEQ ID NO. 8.
  • the second component of the anti-CD 19 maytansinoid immunoconjugate
  • cytotoxic agent refers to a substance that reduces or blocks the function, or growth, of cells and/or causes destruction of cells.
  • the cytotoxic agent is a maytansinoid such as DM4.
  • the cell binding agent of the present invention is covalently attached, directly or via a cleavable or non-cleavable linker, to the cytotoxic agent.
  • the said cell binding agent is conjugated to DM4 through a cleavable linker.
  • this cleavable linker is a SPDB linker.
  • DM4 and a method of conjugating DM4 to the huB4 antibody through a SPDB linker are described in US Patent Publication No. 2004/0235840, which is hereby incorporated by reference.
  • the anti-CD 19 maytansinoid immunoconjugate comprises an antibody which binds specifically to the CD 19 antigen conjugated to DM4 through SPDB wherein about 3.5 molecules of DM4 are bound through the SPDB linker to each antibody molecule.
  • the anti-CD 19 maytansinoid immunoconjugate is
  • Immunoconjugate (1) as depicted in Figure 1. It comprises a light chain and a heavy chain, said light chain having the sequence represented in SEQ ID NO. 7, and said heavy chain having the sequence represented in SEQ ID NO. 8. It further comprises a cytotoxic agent is a maytansinoid such as DM1 or DM4 that is covalently attached, directly or via a cleavable or non-cleavable linker, to the antibody wherein about 3.5 molecules of maytansinoid are bound through the SPDB linker to each antibody molecule.
  • Immunoconjugate (1) comprises a light chain and a heavy chain, said light chain having the sequence represented in SEQ ID NO.
  • the compounds described above are unsolvated.
  • one or both of the compounds used in the method are in solvated form.
  • the solvate can be any of pharmaceutically acceptable solvent, such as water, ethanol, and the like. In general, the presence of a solvate or lack thereof does not have a substantial effect on the efficacy of the PI3K inhibitor or anti-CD 19 maytansinoid immunoconjugate described above.
  • the compound in Formula (1) is depicted in its neutral form, in some embodiments, this compound is used in a pharmaceutically acceptable salt form.
  • the salt can be obtained by any of the methods well known in the art.
  • a "pharmaceutically acceptable salt” of the compound refers to a salt that is pharmaceutically acceptable and that retains pharmacological activity. It is understood that the pharmaceutically acceptable salts are nontoxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington 's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, or S. M. Berge, et al, "Pharmaceutical Salts," J. Pharm. Sci., 1977;66: 1-19, both of which are incorporated herein by reference.
  • Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, as well as those salts formed with organic acids, such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulf
  • the PI3K inhibitor of formula (1) is administered simultaneously with Immunoconjugate (1).
  • Simultaneous administration typically means that both compounds enter the subject at precisely the same time.
  • simultaneous administration also includes the possibility that the PI3K inhibitor and the anti-CD 19 maytansinoid immunoconjugate enter the subject at different times, but the difference in time is sufficiently miniscule that the first administered compound is not provided the time to take effect on the subject before entry of the second administered compound.
  • Such delayed times typically correspond to less than 1 minute, and more typically, less than 30 seconds.
  • simultaneous administration can be achieved by administering a solution containing the combination of compounds.
  • simultaneous administration of separate solutions, one of which contains the PI3K inhibitor and the other of which contains the anti-CD 19 maytansinoid
  • immunoconjugate can be employed.
  • simultaneous administration can be achieved by administering a composition containing the combination of compounds.
  • the anti-CD 19 maytansinoid
  • the anti-CD 19 maytansinoid immunoconjugate and the PI3K inhibitor are administered sequentially.
  • the anti-CD 19 maytansinoid immunoconjugate is administered first, followed immediately thereafter by administration of the PI3K inhibitor.
  • the anti-CD 19 maytansinoid immunoconjugate is administered, a time interval occurs and then the PI3K inhibitor is administered.
  • the time interval can be one or more hour(s), one or more day(s) or one or more week(s).
  • the PI3K inhibitor is administered first, followed immediately thereafter by administration of anti-CD 19 maytansinoid immunoconjugate.
  • the PI3K inhibitor is administered, a time interval occurs and then anti-CD 19 maytansinoid immunoconjugate is administered.
  • one or both of the PI3K inhibitor and anti-CD 19 maytansinoid immunoconjugate are administered in a therapeutically effective (i.e., therapeutic) amount or dosage.
  • a “therapeutically effective amount” is an amount of the PI3K inhibitor or anti-CD 19 maytansinoid immunoconjugate that, when administered to a subject by itself, effectively treats the cancer (for example, decreases the number of lymphoma cells, inhibits tumor growth, stops tumor growth, or causes tumor regression).
  • An amount that proves "therapeutically effective amount" in a given instance, for a particular subject may not be effective for 100% of subjects similarly treated for the disease or condition under consideration, even though such dosage is deemed a "therapeutically effective amount” by skilled practitioners.
  • the amount of the compound that corresponds to a therapeutically effective amount is strongly dependent on the type of cancer, stage of the cancer, the age of the subject being treated, and other facts.
  • one or both of the PI3K inhibitor and the anti-CD 19 maytansinoid immunoconjugate are administered in a sub-therapeutically effective amount or dosage.
  • a sub-therapeutically effective amount is an amount of the PI3K inhibitor or anti- CD 19 maytansinoid immunoconjugate that, when administered to a subject by itself, does not completely inhibit over time the biological activity of the intended target.
  • PI3K inhibitor and anti-CD 19 maytansinoid immunoconjugate should be effective in treating the cancer.
  • a sub -therapeutic amount of anti-CD 19 maytansinoid immunoconjugate can be an effective amount if, when combined with the PI3K inhibitor, the combination is effective in the treatment of a cancer.
  • the combination of compounds exhibits a synergistic effect
  • the combination of compounds can decrease the number of lymphoma cells, inhibit tumor growth, achieve tumor stasis, or even achieve substantial or complete tumor regression.
  • the amounts of anti-CD 19 maytansinoid immunoconjugate and PI3K inhibitor should result in the effective treatment of a cancer
  • the amounts, when combined, are preferably not excessively toxic to the subject (i.e., the amounts are preferably within toxicity limits as established by medical guidelines).
  • Examples of types of cancers to be treated include, but are not limited to, acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin's lymphomas.
  • the subject considered herein is typically a human. However, the subject can be any mammal for which cancer treatment is desired. Thus, the methods described herein can be applied to both human and veterinary applications.
  • treating indicates that the method has, at the least, mitigated abnormal cellular proliferation.
  • the method can reduce the rate of tumor growth in a subject, or prevent the continued growth of a tumor, or even reduce the size of a tumor.
  • terapéuticaally effective amount refers to a sufficient amount of an agent to provide the desired biological, therapeutic, and/or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying, and/or alleviation of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation.
  • an effective amount is an amount sufficient to delay development.
  • an effective amount is an amount sufficient to prevent or delay recurrence.
  • An effective amount can be administered in one or more administrations. The effective amount of the drug or
  • composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer.
  • an "effective amount” for therapeutic uses is the amount of Compound (1) or a pharmaceutically acceptable salt thereof, required to provide a clinically significant decrease in non-Hodgkin lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), or germinal center B-cell like diffuse large B-cell lymphoma (GCB DLBCL).
  • methods for preventing cancer in an animal are provided.
  • prevention denotes causing the clinical symptoms of the disease not to develop in an animal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease.
  • the methods comprise administering to the subject a PI3K inhibitor and an anti-CD 19 maytansinoid immunoconjugate, as described herein.
  • a method of preventing cancer in an animal comprises administering to the animal a compound of Formula (1), or a pharmaceutically acceptable salt thereof, in combination with Immunoconjugate (1).
  • the anti-CD 19 maytansinoid immunoconjugate and PI3K inhibiting compound in pure form or in an appropriate pharmaceutical composition, can be administered via any accepted mode of administration or agents known in the art.
  • the compounds can be administered, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally.
  • the dosage form can be, for example, a solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, pills, soft elastic or hard gelatin capsules, powders, solutions, suspensions, suppositories, aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • a particular route of administration is oral, particularly one in which a convenient daily dosage regimen can be adjusted according to the degree of severity of the disease to be treated.
  • compositions comprising the PI3K inhibitor shown in Formula (1) and the anti-CD 19 maytansinoid immunoconjugate referred to herein as
  • the composition is in the form of a solid (e.g., a powder or tablet) including the PI3K inhibitor in solid form, and optionally, one or more auxiliary (e.g., adjuvant) or pharmaceutically active compounds in solid form.
  • the composition further includes any one or combination of pharmaceutically acceptable carriers (i.e., vehicles or excipients) known in the art, thereby providing a liquid dosage form.
  • pharmaceutically acceptable carriers i.e., vehicles or excipients
  • the components of the combination therapy can also be administered in separate dosage forms.
  • the combination therapy provided herein includes Formula (1) in solid form (e.g., a powder or tablet) and Immunoconjugate (1) in liquid form (e.g., an injectable or intravenous form).
  • Sterile compositions for parenteral administration can be prepared by incorporating the anti-CD 19 maytansinoid immunoconjugate in the required amount in the appropriate solvent, followed by sterilization by micro filtration.
  • solvent or vehicle there may be used water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, as well as a combination thereof.
  • isotonic agents such as sugars, polyalcohols, or sodium chloride in the composition.
  • These compositions may also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents.
  • Sterile compositions for parenteral administration may also be prepared in the form of sterile solid compositions which may be dissolved at the time of use in sterile water or any other injectable sterile medium.
  • Auxiliary and adjuvant agents for the components of the combination therapy may include, for example, preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents.
  • Prevention of the action of microorganisms is generally provided by various antibacterial and antifungal agents, such as, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • Isotonic agents such as sugars, sodium chloride, and the like, may also be included.
  • Prolonged absorption of an injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • the auxiliary agents also can include wetting agents, emulsifying agents, pH buffering agents, and antioxidants, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, and the like.
  • Dosage forms suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They can contain pacifying agents and can be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds also can be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration, whether in a single dosage form or in separate dosage forms, include pharmaceutically acceptable emulsions, solutions,
  • Such dosage forms are prepared, for example, by dissolving, dispersing, etc., the PI3K inhibitor compound described herein, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1 ,3- butyleneglycol, dimethyl formamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol,
  • a carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like
  • Suspensions may contain suspending agents in addition to the active compounds, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents in addition to the active compounds, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds described herein with, for example, suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • Dosage forms for topical administration may include, for example, ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions also can be employed.
  • the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of the compounds described herein, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a pharmaceutically acceptable excipient.
  • the composition will be between about 5% and about 75%> by weight of compounds described herein, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art. Reference is made, for example, to Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990).
  • the composition does not include one or more other anti- cancer compounds. In other embodiments, the composition includes one or more other anticancer compounds.
  • administered compositions can comprise standard of care agents for the type of tumors selected for treatment.
  • kits are provided.
  • Kits according to the invention include package(s) comprising compounds or compositions of the invention.
  • kits comprise Compound (1), or a pharmaceutically acceptable salt thereof, and
  • packaging means any vessel containing compounds or compositions presented herein.
  • the package can be a box or wrapping.
  • Packaging materials for use in packaging pharmaceutical products are well-known to those of skill in the art. Examples of pharmaceutical packaging materials include, but are not limited to, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • the kit also can contain items that are not contained within the package but are attached to the outside of the package, for example, pipettes.
  • Kits can contain instructions for administering compounds or compositions of the invention to a subject. Kits also can comprise instructions for approved uses of compounds herein by regulatory agencies, such as the United States Food and Drug Administration. Kits also can contain labeling or product inserts for the inventive compounds. The package(s) and/or any product insert(s) may themselves be approved by regulatory agencies.
  • the kits can include compounds in the solid phase or in a liquid phase (such as buffers provided) in a package.
  • the kits also can include buffers for preparing solutions for conducting the methods, and pipettes for transferring liquids from one container to another.
  • Compound (1) can be synthesized as described in WO 07/044813, which is hereby incorporated in its entirety.
  • compound (a) a base and an intermediate, compound (a), are added to solution of commercially available 2-metfiyl-2-thiopseudourea sulfate in a solvent such as water and stirred overnight at room temperature. After neutralization, compound (b) is collected by filtration and dried under vacuum. Treatment of compound (b) with POCI 3 and heating at reflux for 2 hours yields compound (c) which can be concentrated under vacuum to dryness.
  • Compound (c) can be used directly in the following reaction with ethylamine carried out in a solvent such as water with heating to give compound (d). Compound (d) is then treated with iodine monochloride in a solvent such as methanol to form compound (e).
  • Compound (f) is then be treated with DBU in the presence of a base, such as DIEA, and heated at reflux for 15 hours. Upon completion of the reaction, the solvent is evaporated and the residue triturated with acetone to yield compound (g). Bromination of compound (g) can be achieved through drop-wise addition of Br 2 to compound (g) in CH 2 C1 2 , followed by stirring overnight at room temperature. Next, filtration is carried out, and triethylamine is added so that, upon washing and drying, the product, compound (h) is obtained.
  • a base such as DIEA
  • compound (i) can be converted to compound (1) of the instant invention through 1) oxidation of the methylthio group with m-CPBA, carried out at room temperature with stirring and 2) treatment of the resulting product dissolved in dioxane, with liquid ammonia.
  • a Pd- catalyst such as [1,1 -bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the presence of a base to yield compound (i).
  • compound (i) can be converted to compound (1) of the instant invention through 1) oxidation of the methylthio group with m-CPBA, carried out at room temperature with stirring and 2) treatment of the resulting product dissolved in dioxane, with liquid ammonia.
  • Immunoconjugate (1) can be prepared as described in, for example, U.S. Patent No. 7,811 ,572, which is hereby incorporated by reference. Briefly, huB4 humanized monoclonal antibody is modified with either (a) a 4.9-fold molar excess of SPDB relative to antibody, or (b) a 4.8-fold molar excess of SPDB relative to antibody. In either situation, reaction proceeds in 50 mM potassium phosphate, 50 mM potassium chloride, and 2 mM EDTA (pH 6.5) in 5% ethanol for a total of 120 minutes at room temperature. The samples are purified over a column of Sephadex.TM.
  • DMA dimethylacetamide
  • Immunoconjugate (1) was evaluated in the cell line OCI-LY7, a specific GCB-DLBCL (germinal center B-cell like diffuse large B-cell lymphoma) cell line. See, e.g., Alvero et al., "Correlation of Capase Activity and Chemo- Response in Epithelial Ovarian Cancer Cell Lines", Promega Notes, pp. 15-17 (2004).
  • the OCI-LY7 cell line was obtained from Cambridge Cell Bank (Cryostock ID 5865, original from DSMZ cell collection ACC688) and grown in IMDM medium (GIBCO cat#31980) supplemented with 20% FCS (GIBCO cat#16140). Cells cultured in flasks were maintained in the atmosphere of 37°C and 5% C02 in a NAPCO Series 8000 DH C02 incubator (Thermo Scientific).
  • Cell treatment was performed in 96-well microtitre assay plates (Costar cat#3904). On the experimental day, cells in exponential growth were harvested and re-suspended in fresh medium, then plated into 96-well plate at an optimal seeding density of 12000 cells/well in 40ul. Medium without cells was used as background control.
  • Cell plate with combination treatments was incubated in the atmosphere of 37°C and 5% C02 in a NAPCO Series 8000 DH C02 incubator (Thermo Scientific) for 24hrs. After treatment, an equal volume (60ul) of Caspase-Glo 3/7 assay solution (Promega cat#8093) was added to each well of cell plate. The cell plate was allowed to incubate at room temperature in the dark (shaking) for 30min before measurement in a luminescent reader (PekinElmer's EnVison 2104 Multilabel Reader).
  • Unprocessed data from the reader were stored in MS Excel file.
  • the first step of data processing was calculating an average background value from the medium control wells (no cells) for each plate. The average background value was then subtracted from each well.
  • the resultant average value from duplicate wells containing cells that had been incubated without compound was considered as 100% of Caspase 3/7 activity.
  • the resultant average value from duplicate wells containing cells with single or combined compounds were compared with data from untreated wells to assess the synergistic effects on cell apoptosis by the compounds.
  • Example 4 In vitro activity of Compound (1) in combination with Immunoconjugate (1) in cell proliferation assay The combination of Immunoconjugate (1) and Compound (1) was evaluated in specific GCB-DLBCL (germinal center B-cell like diffuse large B-cell lymphoma) cell lines OCI-LY7, OCI-LY19, and SU-DHL4.
  • GCB-DLBCL germ center B-cell like diffuse large B-cell lymphoma
  • Compound Dilution Compound stock solution was diluted to 10X of the final treatment concentration (Immunoconjugate (1) starts from 5 ug/ml to 0 ug/ml, Compound (1) from 10 uM to 0 uM) in culture medium with corresponding percentage of Fetal Bovine Serum. Stock compound solution was serially diluted by a factor of 2.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • Biomedical Technology (AREA)
  • Mycology (AREA)
  • Hematology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compositions et méthodes comprenant des inhibiteurs de la voie de la phosphoinositide 3-kinase (PI3K) et des immunoconjugués maytansinoïdes anti-CD19.
PCT/US2013/063983 2012-10-12 2013-10-09 Compositions et méthodes destinées à traiter le cancer à l'aide d'un inhibiteur de pi3k et d'un immunoconjugué maytansinoïde anti-cd19 WO2014058947A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201261713225P 2012-10-12 2012-10-12
US61/713,225 2012-10-12
FR1357035 2013-07-17
FR1357035 2013-07-17

Publications (1)

Publication Number Publication Date
WO2014058947A1 true WO2014058947A1 (fr) 2014-04-17

Family

ID=50477838

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2013/063983 WO2014058947A1 (fr) 2012-10-12 2013-10-09 Compositions et méthodes destinées à traiter le cancer à l'aide d'un inhibiteur de pi3k et d'un immunoconjugué maytansinoïde anti-cd19

Country Status (1)

Country Link
WO (1) WO2014058947A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040235840A1 (en) 2003-05-20 2004-11-25 Immunogen, Inc. Cytotoxic agents comprising new maytansinoids
WO2007044813A1 (fr) 2005-10-07 2007-04-19 Exelixis, Inc. INHIBITEURS DE PI3Kα DE TYPE PYRIDOPYRIMIDINONE
US7811572B2 (en) 2005-08-24 2010-10-12 Immunogen, Inc. Process for preparing purified drug conjugates
WO2012054748A2 (fr) * 2010-10-22 2012-04-26 Seattle Genetics, Inc. Effets synergiques entre des conjugués d'anticorps et de médicament à base d'auristatine et des inhibiteurs de la voie pi3k-akt-mtor
WO2012065019A2 (fr) * 2010-11-12 2012-05-18 Exelixis, Inc. Inhibiteurs pyridopyrimidinone de p13k alpha

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040235840A1 (en) 2003-05-20 2004-11-25 Immunogen, Inc. Cytotoxic agents comprising new maytansinoids
US7811572B2 (en) 2005-08-24 2010-10-12 Immunogen, Inc. Process for preparing purified drug conjugates
WO2007044813A1 (fr) 2005-10-07 2007-04-19 Exelixis, Inc. INHIBITEURS DE PI3Kα DE TYPE PYRIDOPYRIMIDINONE
WO2012054748A2 (fr) * 2010-10-22 2012-04-26 Seattle Genetics, Inc. Effets synergiques entre des conjugués d'anticorps et de médicament à base d'auristatine et des inhibiteurs de la voie pi3k-akt-mtor
WO2012065019A2 (fr) * 2010-11-12 2012-05-18 Exelixis, Inc. Inhibiteurs pyridopyrimidinone de p13k alpha

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING COMPANY
ALVERO ET AL.: "Correlation ofCapase Activity and Chemo-Response in Epithelial Ovarian Cancer Cell Lines", PROMEGA NOTES, 2004, pages 15 - 17
J.A TUSZYNSKI: "SAR-3419", DRUGS OF THE FUTURE, vol. 37, no. 6, 1 June 2012 (2012-06-01), pages 419 - 422, XP055095562, Retrieved from the Internet <URL:http://journals.prous.com/journals/servlet/xmlxsl/dof/20123706/pdf/df370419.pdf?p_JournalId=2&p_refId=1825617&p_IsPs=N> [retrieved on 20140110], DOI: 10.1358/dof.2012.37.6.1825617 *
MARKMAN B ET AL: "216 POSTER A phase I dose-escalation study of the safety, pharmacokinetics and pharmacodynamics of XL765, a novel inhibitor of PI3K and mTOR, administered orally to patients with solid tumors", EUROPEAN JOURNAL OF CANCER. SUPPLEMENT, PERGAMON, OXFORD, GB, vol. 6, no. 12, 1 October 2008 (2008-10-01), pages 68 - 69, XP025534278, ISSN: 1359-6349, [retrieved on 20081001], DOI: 10.1016/S1359-6349(08)72148-7 *
ROGUSKA ET AL., PROC. NATL. ACAD. SCI. USA, vol. 91, 1994, pages 969 - 973
S. M. BERGE ET AL.: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19

Similar Documents

Publication Publication Date Title
Yaghoubi et al. Potential drugs used in the antibody–drug conjugate (ADC) architecture for cancer therapy
JP6581630B2 (ja) 新規ベンゾジアゼピン誘導体
CN111587124B (zh) Ror1抗体免疫缀合物
Shor et al. Preclinical and clinical development of inotuzumab-ozogamicin in hematological malignancies
JP2020152726A (ja) 細胞透過性Ｂｃｌ−ｘＬ阻害剤との抗体薬物コンジュゲート
EP3783025A1 (fr) Anticorps cd73 ciblé et conjugué anticorps-médicament, procédé de préparation associé et utilisations correspondantes
JP2021006527A (ja) 抗ｂ７−ｈ３抗体及び抗体薬物コンジュゲート
CN107530422B (zh) Cd48抗体和其缀合物
CA3027044A1 (fr) Anticorps anti-b7-h3 et conjugues anticorps-medicaments
JP2016514103A (ja) 細胞結合剤及び細胞毒性剤を含む複合体
JP2018507844A (ja) 抗体薬物コンジュゲート
CN105407920A (zh) 靶向癌症、尤其是***癌的合成性抗体模拟化合物(SyAMs)
US20230110128A1 (en) Use of antibody drug conjugates comprising tubulin disrupting agents to treat solid tumor
US20210261505A1 (en) Linker, Antibody-Drug Conjugate Including Same and Use Thereof
JP2019534889A (ja) 抗体−ポリマー−薬物コンジュゲート
IL297167A (en) Charging variant connectors
US20240026028A1 (en) Anti-her3 antibody and anti-her3 antibody-drug conjugate and medical use thereof
JP2023036874A (ja) イムノコンジュゲートにおけるメチオニン酸化を防止する方法
CN112512583B (zh) 酞菁染料偶联物组合物
JP5478492B2 (ja) 医薬化合物
WO2014058947A1 (fr) Compositions et méthodes destinées à traiter le cancer à l&#39;aide d&#39;un inhibiteur de pi3k et d&#39;un immunoconjugué maytansinoïde anti-cd19
WO2023024949A1 (fr) Conjugué anticorps-médicament conjugué par l&#39;intermédiaire d&#39;un lieur cassable
CN116036303A (zh) 一种抗体-药物偶联物及其制备方法和应用
CN110759940A (zh) 连接子、含连接子的抗体偶联药物及连接子的用途
KR102400031B1 (ko) 항종양 면역 상승효과를 나타내는 종양세포 특이적 자가조립 나노입자

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13784057

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13784057

Country of ref document: EP

Kind code of ref document: A1