WO2022097090A1 - Schéma posologique et polythérapies avec des anticorps multispécifiques ciblant un antigène de maturation des lymphocytes b et des inhibiteurs de gamma secrétase - Google Patents

Schéma posologique et polythérapies avec des anticorps multispécifiques ciblant un antigène de maturation des lymphocytes b et des inhibiteurs de gamma secrétase Download PDF

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WO2022097090A1
WO2022097090A1 PCT/IB2021/060276 IB2021060276W WO2022097090A1 WO 2022097090 A1 WO2022097090 A1 WO 2022097090A1 IB 2021060276 W IB2021060276 W IB 2021060276W WO 2022097090 A1 WO2022097090 A1 WO 2022097090A1
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dose
subject
administered
gsi
binding molecule
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Kimberly Marie AARDALEN
Lulu Chu
Serena DE VITA
Mirek DOSTALEK
Sema KURTULUS
Haihui Lu
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Novartis Ag
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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
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07K16/2878—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 NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • 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
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • BCMA antibodydrug conjugates such as GSK2857916 (GlaxoSmithkline) and bispecific BCMA binding molecules targeting BMCA and CD3 such as PF06863135 (Pfizer), EM 901 (EngMab), JNJ- 64007957 (Janssen), and AMG 420 (Amgen). See, Cho et al., 2018, Front Immunol. 9:1821 ; WO 2016/0166629.
  • polypeptides e.g., antibodies and multispecific binding molecules, which bind BCMA, and which have an improved safety profile (e.g., decreasing cytokine release) while still retaining a high efficacy.
  • the GSi is adminstered at a dose of about 0.9 mg. In some embodiments, the GSi is adminstered at a dose of about 2 mg. In some embodiments, the GSi is adminstered at a dose of about 4 mg. In some embodiments, the GSi is adminstered at a dose of about 6 mg. In some embodiments, the GSi is adminstered twice a week, as a first GSi dose and a second GSi dose. In some embodiments, the first GSi dose and the second GSI dose are adminstered on two consecutive days. In some embodiments, the first GSi dose and the second GSI dose are adminstered on the same day.
  • the first GSi dose and the second GSI dose are adminstered on two non-consecutive days. In some embodiments, the first GSi dose is adminstered about 24 hours prior the second GSi dose. In some embodiments, after the second GSi dose is adminstered to the subject, the GSi is not readminstered for at least 5 consecutive days. In some embodiments, the first GSi dose is administered to the subject one day before the BCMA binding molecule is adminstered. In some embodiments, the second GSi dose is administered to the subject on the same day as the BCMA binding molecule.
  • the BCMA bispecific antibody is administered to the subject at a dose of about 12 pg/kg and the first and/or second GSi dose is administered to the subject at a dose of about 2 mg. In some embodiments, the BCMA bispecific antibody is administered to the subject at a dose of about 24 pg/kg and the first and/or second GSi dose is administered to the subject at a dose of about 2 mg. In some embodiments, the BCMA bispecific antibody is administered to the subject at a dose of about 48 pg/kg and the first and/or second GSi dose is administered to the subject at a dose of about 2 mg.
  • the BCMA bispecific antibody is administered to the subject at a dose of about 48 pg/kg and the first and/or second GSi dose is administered to the subject at a dose of about 4 mg. In some embodiments, the BCMA bispecific antibody is administered to the subject at a dose of about 96 pg/kg and the first and/or second GSi dose is administered to the subject at a dose of about 4 mg. In some embodiments, the BCMA bispecific antibody is administered to the subject at a dose of about 192 pg/kg and the first and/or second GSi dose is administered to the subject at a dose of about 4 mg.
  • the BCMA binding molecule is a CAR-T. In some embodiments, the BCMA binding molecule is RLT.
  • the multiple myeloma is relapsed. In some embodiments, the multiple myeloma is refractory.
  • the BCMA binding molecule is administered to the subject intravenously. In some embodiments, the BCMA binding molecule is administered to the subject as an infusion. In some embodiments, the infusion can be performed over a 1 .5 - 3 hour span. In some embodiments, the infusion is over a 2 hour span.
  • the method further comprises adminstering to the subject one or more additional therapeutic agents.
  • the additional therapeutic agents can be antidiarrehals (e.g., loperamide), octreotide, glucocorticoids (e.g, prednisone, cortisone, dexamethasone), emollients, antibiotics, paracetamol, acetaminophen, antihistamines, anti-T cell directed therapy, or any combiniation thereof.
  • the one or more additional therapeutic agents reduces a side effect of the GSi and/or the BCMA binding molecule.
  • the side effect is cytokine release syndrome (CRS).
  • the subject has been previously treated with at least two prior treatment regimens.
  • FIG. 3 shows that RTCC assay represents the most sensitive in vitro functional assays.
  • EC30 values for BSBM3 were plotted for three different types of in vitro functional assays, RTCC, T cell proliferation and cytokine production (as shown in FIG. 2).
  • Each data point represents one of nine biological replicates (T cells from three healthy donors were tested individually, each in three independent experiments).
  • FIG. 4 shows that soluble BCMA decreases the activity of BSBM3 in RTCC assay.
  • the EC30 values for BSBM3 in RTCC assays with added soluble BCMA as indicated are shown. Each data point represents one of nine biological replicates (T cells from three healthy donor T cells were tested individually, each in three independent experiments).
  • FIG. 5 shows the anti-tumor activity of BSBM3 on KMS11 xenograft in a human PBMC adoptive transfer mouse model.
  • NSG mice were inoculated with KMS11 cells via tail vein injection on Day 0 (DO), adoptively transferred with PBMCs on D7, and treated on D15 with the following doses of BSBM3: 0.03 mg/kg (triangle), 0.3 mg/kg (circle) or 3.0 mg/kg (diamond).
  • tumor bearing mice without human PBMCs incrementasing circles
  • tumor-bearing mice with human PBMCs but no Ab treatment squares.
  • the result from one representative experiment is shown from three biological replicates. *p ⁇ 0.05, Dunnett’s multiple comparison test. Data are expressed as the geometric mean +/- SEM from 5 mice per group.
  • FIG. 7 shows the international staging system for the BSBM3 clinical trial.
  • FIG. 10 shows BSBM3 mediated RTCC activity assayed in the presence of 8nM BSBM3.
  • BSBM3 was added at 1 :5 serial dilutions across ten points starting from 10 nM.
  • the average RTCC activity (mean+Z-SEM) from three independent RTCC assays (using three different healthy donor T cells) were plotted against BSBM3 concentrations in the presence of 8nM BSBM3.
  • FIG. 11 shows the different dose levels of the BCMA binding molecule in combiniation with the proposed GSi.
  • the present disclosure provides methods of treating and/or preventing a disease (e.g., cancer) comprising administering to a subject in need thereof a composition comprising a BCMA binding molecule, particularly the BCMA binding molecule designated as BSBM3, as well as a gamma secretase inhibitor (GSi).
  • a disease e.g., cancer
  • the methods further comprise administering one or more therapeutic agents, e.g., one or more anti-tumor agents.
  • the disclosure further provides formulations, dosing, dosing regimens and schedules, biomarkers, pharmaceutical combinations, and other relevant clinical features.
  • the one or more therapeutic agents can be a PD-1 inhibitor, a LAG-3 inhibitor, a cytokine, an A2A antagonist, a GITR agonist, a TIM-3 inhibitor, a STING agonist, and a TLR7 agonist, for treating and/or preventing a patient/subject with cancer.
  • ADCC antibody dependent cell-mediated cytotoxicity
  • ADCP antibody dependent cell-mediated phagocytosis as used herein is meant the cell-mediated reaction where nonspecific phagocytic cells that express FcyRs recognize bound antibody on a target cell and subsequently cause phagocytosis of the target cell.
  • Additional Agent For convenience, an agent that is used in combination with an antigen-binding molecule of the disclosure is referred to herein as an “additional” agent.
  • Antibody refers to a polypeptide (or set of polypeptides) of the immunoglobulin family that is capable of binding an antigen non-covalently, reversibly and specifically.
  • a naturally occurring “antibody” of the IgG type is a tetramer comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region.
  • VH heavy chain variable 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 VL) and a light chain constant region.
  • the light chain constant region is comprised of one domain (abbreviated herein as CL).
  • CL light chain constant region
  • 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 regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FRs arranged from amino-terminus to carboxy-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 term “antibody” includes, but is not limited to, monoclonal antibodies, human antibodies, humanized antibodies, camelised antibodies, chimeric antibodies, bispecific or multispecific antibodies and anti-idiotypic (anti-ld) antibodies (including, e.g., anti-ld antibodies to antibodies of the disclosure).
  • the antibodies can be of any isotype/class (e.g., IgG, IgE, IgM, IgD, IgA and IgY) or subclass (e.g., lgG1 , lgG2, lgG3, lgG4, lgA1 and lgA2).
  • variable domains of both the light (VL) and heavy (VH) chain portions determine antigen recognition and specificity.
  • the constant domains of the light chain (CL) and the heavy chain (CH1 , CH2 or CH3) confer important biological properties such as secretion, transplacental mobility, Fc receptor binding, complement binding, and the like.
  • the numbering of the constant region domains increases as they become more distal from the antigen-binding site or amino-terminus of the antibody.
  • at the N-terminus is a variable region and at the C-terminus is a constant region; the CH3 and CL domains actually comprise the carboxy-terminus of the heavy and light chain, respectively.
  • Antibody fragment refers to one or more portions of an antibody. In some embodiments, these portions are part of the contact domain(s) of an antibody. In some other embodiments, these portion(s) are antigenbinding fragments that retain the ability of binding an antigen non-covalently, reversibly and specifically, sometimes referred to herein as the “antigen-binding fragment”, “antigen-binding fragment thereof,” “antigen-binding portion”, and the like.
  • binding fragments include, but are not limited to, single-chain Fvs (scFv), a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CH1 domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment (Ward et al., 1989, Nature 341 :544-546), which consists of a VH domain; and an isolated complementarity determining region (CDR).
  • scFv single-chain Fvs
  • Fab fragment a monovalent fragment consisting of the VL, VH, CL and CH1 domains
  • F(ab)2 fragment a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region
  • antibody fragment encompasses both proteolytic fragments of antibodies (e.g., Fab and F(ab)2 fragments) and engineered proteins comprising one or more portions of an antibody (e.g., an scFv).
  • Antibody fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, 2005, Nature Biotechnology 23: 1126-1136).
  • Antibody fragments can be grafted into scaffolds based on polypeptides such as Fibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide monobodies).
  • Fn3 Fibronectin type III
  • Antigen-binding domain refers to a portion of an antigen-binding molecule that has the ability to bind to an antigen non-covalently, reversibly and specifically.
  • Exemplary ABDs include antigen-binding fragments and portions of both immunoglobulin and non-immunoglobulin based scaffolds that retain the ability of binding an antigen non-covalently, reversibly and specifically.
  • the term “antigenbinding domain” encompasses antibody fragments that retain the ability of binding an antigen non-covalently, reversibly and specifically.
  • Antigen-binding domain chain or ABD chain Individual ABDs can exist as one (e.g., in the case of an scFv) polypeptide chain or form through the association of more than one polypeptide chains (e.g., in the case of a Fab).
  • the term “ABD chain” refers to all or a portion of an ABD that exists on a single polypeptide chain. The use of the term “ABD chain” is intended for convenience and descriptive purposes only and does not connote a particular configuration or method of production.
  • Antigen-binding fragment refers to a portion of an antibody that retains has the ability to bind to an antigen non-covalently, reversibly and specifically.
  • Antigen-binding molecule refers to a molecule comprising one or more antigen-binding domains, for example an antibody.
  • the antigenbinding molecule can comprise one or more polypeptide chains, e.g., one, two, three, four or more polypeptide chains.
  • the polypeptide chains in an antigen-binding molecule can be associated with one another directly or indirectly (for example a first polypeptide chain can be associated with a second polypeptide chain which in turn can be associated with a third polypeptide chain to form an antigen-binding molecule in which the first and second polypeptide chains are directly associated with one another, the second and third polypeptide chains are directly associated with one another, and the first and third polypeptide chains are indirectly associated with one another through the second polypeptide chain).
  • association in the context of domains or regions within an antigen-binding molecule refers to a functional relationship between two or more polypeptide chains and/or two or more portions of a single polypeptide chain.
  • association means that two or more polypeptides (or portions of a single polypeptide) are associated with one another, e.g., non-covalently through molecular interactions and/or covalently through one or more disulfide bridges or chemical cross-linkages, so as to produce a functional antigen-binding domain.
  • B cell refers to a cell of B cell lineage, which is a type of white blood cell of the lymphocyte subtype.
  • B cells include plasmablasts, plasma cells, lymphoplasmacytoid cells, memory B cells, follicular B cells, marginal zone B cells, B-1 cells, B-2 cells, and regulatory B cells.
  • B cell malignancy refers to an uncontrolled proliferation of B cells.
  • B cell malignancy include non-Hodgkin’s lymphomas (NHL), Hodgkin’s lymphomas, leukemia, and myeloma.
  • a B cell malignancy can be, but is not limited to, multiple myeloma, chronic lymphocytic leukemia (CLL)Zsmall lymphocytic lymphoma (SLL), follicular lymphoma, mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), marginal zone lymphomas, Burkitt lymphoma, lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia), hairy cell leukemia, primary central nervous system (CNS) lymphoma, primary mediastinal large B-cell lymphoma, mediastinal grey-zone lymphoma (MGZL), splenic marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma of MALT, nodal marginal zone B-cell lymphoma, and primary effusion lymphoma, and plasmacytic dendritic cell neoplasms.
  • CLL chronic lymphocytic leuk
  • BCMA B-cell maturation antigen
  • BCMA also known as TNFRSF17, BCM or CD269
  • TNFRSF17 BCM
  • CD269 B-cell maturation antigen
  • BAFF B-cell activating factor
  • APRIL proliferationinducing ligand
  • the protein BCMA is encoded by the gene TNFRSF17. Exemplary BCMA sequences are available at the Uniprot database under accession number Q02223.
  • BCMA binding molecule refers to a molecule that specifically binds to BCMA, particularly human BCMA.
  • BCMA binding molecules including multispecific binding molecules that comprise at least one ABD that binds to BCMA, e.g., multispecific antibodies, bispecific antibodies and other bispecific binding molecules.
  • a particular BCMA binding molecule of the disclosure is referred to herein as BSBM3.
  • Bispecific binding molecule refers to a molecule that specifically binds to two antigens and comprises two or more ABDs.
  • the BBMs of the disclosure comprise at least one antigen-binding domain which is specific for BCMA and at least one antigen-binding domain which is specific for a different antigen, e.g., component of a TCR complex. Representative BBMs are illustrated in FIG. 1 B-1AG. BBMs can comprise one, two, three, four or even more polypeptide chains.
  • Bivalent refers to an antigen-binding molecule that has two ABDs. The domains can be the same or different. Accordingly, a bivalent antigen-binding molecule can be monospecific or bispecific. Bivalent BBMs comprise an ABD that specifically binds to BCMA and another ABD that binds to another antigen, e.g., a component of the TCR complex.
  • BSBM3 refers to a BCMA binding molecule comprising (a) a first polypeptide whose amino acid sequence comprises the amino acid sequence of SEQ ID NO:1 ; (b) a second polypeptide whose amino acid sequence comprises the amino acid sequence of SEQ ID NO:2; and (c) a third polypeptide whose amino acid sequence comprises the amino acid sequence of SEQ ID NO:3.
  • the first, second and third polypeptide associate to form a binding molecule with the configuration shown in FIG. 1 .
  • cancer refers to a disease characterized by the uncontrolled (and often rapid) growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein and include but are not limited to, leukemia, multiple myeloma, asymptomatic myeloma, Hodgkin’s lymphoma and non-Hodgkin’s lymphoma, e.g., any BCMA-positive cancers of any of the foregoing types.
  • cancer cancer refers to a B cell that is undergoing or has undergone uncontrolled proliferation
  • CD3 refers to the cluster of differentiation 3 co-receptor of the T cell receptor.
  • CD3 helps in activation of both cytotoxic T-cell (e.g., CD8+ naive T cells) and T helper cells (e.g., CD4+ naive T cells) and is composed of four distinct chains: one CD3y chain (e.g., Genbank Accession Numbers NM_000073 and MP_000064 (human)), one CD36 chain (e.g., Genbank Accession Numbers NM_000732, NM_001040651 , NP_00732 and NP_001035741 (human)), and two CD3s chains (e.g., Genbank Accession Numbers NM_000733 and NP_00724 (human)).
  • CD3y chain e.g., Genbank Accession Numbers NM_000073 and MP_000064 (human)
  • CD36 chain e.g., Genbank Accession Numbers NM_000732, NM_
  • the chains of CD3 are highly related cellsurface proteins of the immunoglobulin superfamily containing a single extracellular immunoglobulin domain.
  • the CD3 molecule associates with the T-cell receptor (TCR) and - chain to form the T-cell receptor (TCR) complex, which functions in generating activation signals in T lymphocytes.
  • TCR T-cell receptor
  • TCR T-cell receptor
  • the reference to CD3 in the application can refer to the CD3 co-receptor, the CD3 co-receptor complex, or any polypeptide chain of the CD3 co-receptor complex.
  • Chimeric Antibody is an antibody molecule (or antigen-binding fragment thereof) in which (a) the constant region, or a portion thereof, is altered, replaced or exchanged so that the antigen-binding site (variable region) is linked to a constant region of a different or altered class, effector function and/or species, or an entirely different molecule which confers new properties to the chimeric antibody, e.g., an enzyme, toxin, hormone, growth factor, drug, etc.; or (b) the variable region, or a portion thereof, is altered, replaced or exchanged with a variable region having a different or altered antigen specificity.
  • a mouse antibody can be modified by replacing its constant region with the constant region from a human immunoglobulin. Due to the replacement with a human constant region, the chimeric antibody can retain its specificity in recognizing the antigen while having reduced antigenicity in human as compared to the original mouse antibody.
  • Complementarity determining region refers to the sequences of amino acids within antibody variable regions which confer antigen specificity and binding affinity. For example, in general, there are three CDRs in each heavy chain variable region (e.g., CDR-H1 , CDR-H2, and CDR- H3) and three CDRs in each light chain variable region (CDR-L1 , CDR-L2, and CDR-L3).
  • CDR-H1 , CDR-H2, and CDR- H3 three CDRs in each light chain variable region
  • CDR-L1 , CDR-L2, and CDR-L3 three CDRs in each light chain variable region.
  • the precise amino acid sequence boundaries of a given CDR can be determined using any one of a number of well-known schemes, including those described by Kabat et al., 1991 , “Sequences of Proteins of Immunological Interest,” 5th Ed.
  • IMGT ImMunoGenTics
  • the CDRs correspond to the amino acid residues that are defined as part of the Kabat CDR, together with the amino acid residues that are defined as part of the Chothia CDR.
  • the CDRs defined according to the “Chothia” number scheme are also sometimes referred to as “hypervariable loops.”
  • CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (CDR-H1) (e.g., insertion(s) after position 35), 50-65 (CDR- H2), and 95-102 (CDR-H3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (CDR-L1) (e.g., insertion(s) after position 27), 50-56 (CDR-L2), and 89-97 (CDR-L3).
  • the CDR amino acids in the VH are numbered 26-32 (CDR-H1) (e.g., insertion(s) after position 31), 52-56 (CDR-H2), and 95-102 (CDR-H3); and the amino acid residues in VL are numbered 26-32 (CDR-L1) (e.g., insertion(s) after position 30), 50-52 (CDR-L2), and 91-96 (CDR-L3).
  • the CDRs comprise or consist of, e.g., amino acid residues 26-35 (CDR-H1), 50-65 (CDR-H2), and 95-102 (CDR-H3) in human VH and amino acid residues 24- 34 (CDR-L1), 50-56 (CDR-L2), and 89-97 (CDR-L3) in human VL.
  • Concurrently is not limited to the administration of therapies (e.g., prophylactic or therapeutic agents) at exactly the same time, but rather it is meant that a pharmaceutical composition comprising an antigen-binding molecule is administered to a subject in a sequence and within a time interval such that the molecules can act together with the additional therapy(ies) to provide an increased benefit than if they were administered otherwise.
  • therapies e.g., prophylactic or therapeutic agents
  • one or more amino acid residues within a BBM can be replaced with other amino acid residues from the same side chain family and the altered BBM can be tested for, e.g., binding to target molecules and/or effective heterodimerization and/or effector function.
  • Binding of antibody to Fc receptors on cell surfaces triggers a number of important and diverse biological responses including engulfment and destruction of antibody-coated particles, clearance of immune complexes, ADCC, ADCP, release of inflammatory mediators, placental transfer and control of immunoglobulin production.
  • An effector function of an antibody can be altered by altering, e.g., enhancing or reducing, the affinity of the antibody for an effector molecule such as an Fc receptor or a complement component. Binding affinity will generally be varied by modifying the effector molecule binding site, and in this case it is appropriate to locate the site of interest and modify at least part of the site in a suitable way.
  • an alteration in the binding site on the antibody for the effector molecule need not alter significantly the overall binding affinity but can alter the geometry of the interaction rendering the effector mechanism ineffective as in non-productive binding. It is further envisaged that an effector function can also be altered by modifying a site not directly involved in effector molecule binding, but otherwise involved in performance of the effector function.
  • Fab domains are formed by association of a CH1 domain attached to a VH domain with a CL domain attached to a VL domain.
  • the VH domain is paired with the VL domain to constitute the Fv region, and the CH1 domain is paired with the CL domain to further stabilize the binding module.
  • a disulfide bond between the two constant domains can further stabilize the Fab domain.
  • Fc region The term “Fc region” or “Fc chain” as used herein is meant the polypeptide comprising the CH2-CH3 domains of an IgG molecule, and in some cases, inclusive of the hinge. In EU numbering for human lgG1 , the CH2-CH3 domain comprises amino acids 231 to 447, and the hinge is 216 to 230. Thus the definition of “Fc region” includes both amino acids 231-447 (CH2-CH3) or 216-447 (hinge-CH2-CH3), or fragments thereof.
  • an “Fc fragment” in this context can contain fewer amino acids from either or both of the N- and C-termini but still retains the ability to form a dimer with another Fc region as can be detected using standard methods, generally based on size (e.g., non-denaturing chromatography, size exclusion chromatography).
  • Human IgG Fc regions are of particular use in the present disclosure, and can be the Fc region from human IgG 1 , lgG2 or lgG4.
  • Fc domain refers to a pair of associated Fc regions. The two Fc regions dimerize to create the Fc domain. The two Fc regions within the Fc domain can be the same (such an Fc domain being referred to herein as an “Fc homodimer”) or different from one another (such an Fc domain being referred to herein as an “Fc heterodimer”).
  • Fv The term “Fv”, “Fv fragment” or “Fv region” refer to a region that comprises the VL and VH domains of an antibody fragment in a tight, noncovalent association (a VH-VL dimer). It is in this configuration that the three CDRs of each variable domain interact to define a target binding site. Often, the six CDRs confer target binding specificity to an antigen-binding molecule. However, in some instances even a single variable domain (or half of an Fv comprising only three CDRs specific for a target) can have the ability to recognize and bind target.
  • VH and VL of an Fv are on separate polypeptide chains but can be engineered as a single chain Fv (scFv).
  • the terms also include Fvs that are engineered by the introduction of disulfide bonds for further stability.
  • VH-VL dimer herein is not intended to convey any particular configuration.
  • the VH can be N-terminal or C-terminal to the VL (with the VH and VL typically connected by a linker as discussed herein).
  • Half Antibody refers to a molecule that comprises at least one ABD or ABD chain and can associate with another molecule comprising an ABD or ABD chain through, e.g., a disulfide bridge or molecular interactions (e.g., knob-in-hole interactions between Fc heterodimers).
  • a half antibody can be composed of one polypeptide chain or more than one polypeptide chains (e.g., the two polypeptide chains of a Fab).
  • a half-antibody comprises an Fc region.
  • a half antibody is a molecule comprising a heavy and light chain of an antibody (e.g., an IgG antibody).
  • Another example of a half antibody is a molecule comprising a first polypeptide comprising a VL domain and a CL domain, and a second polypeptide comprising a VH domain, a CH1 domain, a hinge domain, a CH2 domain, and a CH3 domain, where the VL and VH domains form an ABD.
  • Yet another example of a half antibody is a polypeptide comprising an scFv domain, a CH2 domain and a CH3 domain.
  • a half antibody might include more than one ABD, for example a half-antibody comprising (in N- to C-terminal order) an scFv domain, a CH2 domain, a CH3 domain, and another scFv domain.
  • Half antibodies might also include an ABD chain that when associated with another ABD chain in another half antibody forms a complete ABD.
  • a BBM can comprise one, more typically two, or even more than two half antibodies, and a half antibody can comprise one or more ABDs or ABD chains.
  • a first half antibody will associate, e.g., heterodimerize, with a second half antibody.
  • a first half antibody will be covalently linked to a second half antibody, for example through disulfide bridges or chemical crosslinking.
  • a first half antibody will associate with a second half antibody through both covalent attachments and non-covalent interactions, for example disulfide bridges and knob-in-hole interactions.
  • half antibody is intended for descriptive purposes only and does not connote a particular configuration or method of production. Descriptions of a half antibody as a “first” half antibody, a “second” half antibody, a “left” half antibody, a “right” half antibody or the like are merely for convenience and descriptive purposes.
  • Host cell or recombinant host cell refer to a cell that has been genetically-engineered, e.g., through introduction of a heterologous nucleic acid. It should be understood that such terms are intended to refer not only to the particular subject cell but to the progeny of such a cell. Because certain modifications can occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term “host cell” as used herein.
  • a host cell can carry the heterologous nucleic acid transiently, e.g., on an extrachromosomal heterologous expression vector, or stably, e.g., through integration of the heterologous nucleic acid into the host cell genome.
  • a host cell can be a cell line of mammalian origin or mammalian-like characteristics, such as monkey kidney cells (COS, e.g., COS-1 , COS- 7), HEK293, baby hamster kidney (BHK, e.g., BHK21), Chinese hamster ovary (CHO), NSO, PerC6, BSC-1 , human hepatocellular carcinoma cells (e.g., Hep G2), SP2/0, HeLa, Madin-Darby bovine kidney (MDBK), myeloma and lymphoma cells, or derivatives and/or engineered variants thereof.
  • the engineered variants include, e.g., glycan profile modified and/or site-specific integration site derivatives.
  • humanized forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin.
  • humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having the desired specificity, affinity, and capacity.
  • donor antibody such as mouse, rat, rabbit or non-human primate having the desired specificity, affinity, and capacity.
  • framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • humanized antibodies can comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin Io sequence.
  • the humanized antibody optionally will also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • Humanized antibodies are typically less immunogenic to humans, relative to non-humanized antibodies, and thus offer therapeutic benefits in certain situations. Humanized antibodies can be generated using known methods. See for example, Hwang et al., 2005, Methods 36:35; Queen et al., 1989, Proc. Natl. Acad. Sci.
  • Human Antibody includes antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Furthermore, if the antibody contains a constant region, the constant region also is derived from such human sequences, e.g., human germline sequences, or mutated versions of human germline sequences or antibody containing consensus framework sequences derived from human framework sequences analysis, for example, as described in Knappik et al., 2000, J Mol Biol 296, 57-86.
  • immunoglobulin variable domains e.g., CDRs
  • CDRs can be defined using well known numbering schemes, e.g., the Kabat numbering scheme, the Chothia numbering scheme, or any combination of Kabat and Chothia (see, e.g., Lazikani et al., 1997, J. Mol. Bio. 273:927 948; Kabat et al., 1991 , Sequences of Proteins of Immunological Interest, 5th edit., NIH Publication no. 91-3242 U.S. Department of Health and Human Services; Chothia et al., 1987, J. Mol. Biol. 196:901-917; Chothia et al., 1989, Nature 342:877-883).
  • Human antibodies can include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo, or a conservative substitution to promote stability or manufacturing).
  • human antibody as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • Administered “in combination,” as used herein, means that two (or more) different treatments are delivered to the subject during the course of the subject’s affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons.
  • Knob In the context of a knob-into-hole, a “knob” refers to at least one amino acid side chain which projects from the interface of a first Fc chain and is therefore positionable in a compensatory “hole” in the interface with a second Fc chain so as to stabilize the Fc heterodimer, and thereby favor Fc heterodimer formation over Fc homodimer formation, for example.
  • Monoclonal Antibody refers to polypeptides, including antibodies, antibody fragments, molecules (including BBMs), etc. that are derived from the same genetic source.
  • Monovalent The term “monovalent” as used herein in the context of an antigenbinding molecule refers to an antigen-binding molecule that has a single antigen-binding domain.
  • Multispecific binding molecule refers to an antigen-binding molecule that specifically binds to at least two antigens and comprises two or more ABDs.
  • the ABDs can each independently be an antibody fragment (e.g., scFv, Fab, nanobody), a ligand, or a non-antibody derived binder (e.g., fibronectin, Fynomer, DARPin).
  • nucleic acid is used herein interchangeably with the term “polynucleotide” and refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form.
  • the term encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides.
  • Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, and peptidenucleic acids (PNAs).
  • nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions) and complementary sequences, as well as the sequence explicitly indicated.
  • degenerate codon substitutions can be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzer et al., (1991) Nucleic Acid Res. 19:5081 ; Ohtsuka et al., (1985) J. Biol. Chem. 260:2605-2608; and Rossolini et al., (1994) Mol. Cell. Probes 8:91-98).
  • operably linked refers to a functional relationship between two or more peptide or polypeptide domains or nucleic acid (e.g., DNA) segments.
  • nucleic acid e.g., DNA
  • operably linked means that two or more amino acid segments are linked so as to produce a functional polypeptide.
  • ABMs or chains of an ABM
  • operably linked means that the two nucleic acids are joined such that the amino acid sequences encoded by the two nucleic acids remain in-frame.
  • transcriptional regulation the term refers to the functional relationship of a transcriptional regulatory sequence to a transcribed sequence.
  • a promoter or enhancer sequence is operably linked to a coding sequence if it stimulates or modulates the transcription of the coding sequence in an appropriate host cell or other expression system.
  • polypeptide and Protein are used interchangeably herein to refer to a polymer of amino acid residues.
  • the terms encompass amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer. Additionally, the terms encompass amino acid polymers that are derivatized, for example, by synthetic derivatization of one or more side chains or termini, glycosylation, PEGylation, circular permutation, cyclization, linkers to other molecules, fusion to proteins or protein domains, and addition of peptide tags or labels.
  • Recognize refers to an ABD that finds and interacts (e.g., binds) with its epitope.
  • Single Chain Fab or scFab The terms “single chain Fab” and “scFab” mean a polypeptide comprising an antibody heavy chain variable domain (VH), an antibody constant domain 1 (CH1), an antibody light chain variable domain (VL), an antibody light chain constant domain (CL) and a linker, such that the VH and VL are in association with one another and the CH1 and CL are in association with one another.
  • the antibody domains and the linker have one of the following orders in N-terminal to C-terminal direction: a) VH-CH1- linker-VL-CL, b) VL-CL-linker-VH-CH1 , c) VH-CL-linker-VL-CH1 or d) VL-CH1 -linker- VH-CL.
  • the linker can be a polypeptide of at least 30 amino acids, e.g., between 32 and 50 amino acids.
  • the single chain Fabs are stabilized via the natural disulfide bond between the CL domain and the CH1 domain.
  • the delivery of one treatment is still occurring when the delivery of a second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery”.
  • the treatment is more effective because of combined administration.
  • the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment.
  • delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other.
  • the effect of the two treatments can be partially additive, wholly additive, or greater than additive.
  • the delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.
  • Single Chain Fv or scFv By “single chain Fv” or “scFv” herein is meant a variable heavy domain covalently attached to a variable light domain, generally using an ABD linker as discussed herein, to form a scFv or scFv domain.
  • a scFv domain can be in either orientation from N- to C-terminus (VH-linker-VL or VL-linker-VH).
  • Specifically (or selectively) binds refers to a binding reaction that is determinative of the presence of a cognate antigen or an epitope in a heterogeneous population of proteins and other biologies.
  • formulations of BCMA binding molecules can be prepared by mixing BCMA binding molecules with physiologically acceptable carriers, excipients, or stabilizers in the form of, e.g., lyophilized powders, slurries, aqueous solutions, lotions, or suspensions (see, e.g., Hardman et al., 2001 , Goodman and Gilman’s The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y.; Gennaro, 2000, Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, N.Y.; Avis et al.
  • the BCMA binding molecule can be formulated with one or more excipients.
  • the BCMA binding molecule is formulated with an amino acid.
  • the BCMA binding molecule is formulated with a sugar.
  • the BCMA binding molecule is formulated with a surfactant.
  • the BCMA binding molecule is formulated with water.
  • the BCMA binding molecule can be formulated with one or more of an amino acid, a sugar, or a surfactant.
  • the amino acid can be histidine.
  • the sugar can be sucrose.
  • the surfactant can be polysorbate, such as polysorbate 20 (“PS20”), also known as Tween 20.
  • compositions comprising a BCMA binding molecule and (a) an amino acid such as histidine; (b) a sugar such as sucrose; (c) a surfactant such as PS20 ; or (d) a combination of any two or all of the foregoing.
  • an amino acid such as histidine
  • a sugar such as sucrose
  • a surfactant such as PS20
  • the pharmaceutical composition can be a liquid pharmaceutical composition.
  • Suitable concentrations of histidine range from 10 mM to 50 mM. In an embodiment, the concentration of histidine is 20 mM.
  • Suitable concentrations of sucrose range from 150 mM to 300 mM. In an embodiment, the concentration of sucrose is 240 mM.
  • Suitable concentrations of PS20 range from 0.02% to 0.06%. In an embodiment, the concentration of PS20 is 0.04%.
  • the pharmaceutical composition can be lyophilized and reconstituted in a suitable volume of liquid to obtain a solution for administration containing one or more of histidine, sucrose and PS20, e.g., in the concentrations described above.
  • a suitable concentration range for the BCMA binding molecule is between 5 mg/mL and 20 mg/mL, and in an embodiment is 10 mg/mL.
  • the GSi of the disclosure can be formulated in a variety of manners.
  • the GSi can be formulated so as to be adminstered orally.
  • the GSi can be formulated as liquid.
  • the GSi can be formulated into a capsule.
  • the subject can be dosed with the BCMA binding molecule with about 0.5 pg/kg. In some embodiments, the subject can be dosed with the BCMA binding molecule with about 1 pg/kg. In some embodiments, the subject can be dosed with the BCMA binding molecule with about 10 pg/kg. In some embodiments, the subject can be dosed with the BCMA binding molecule with about 30 pg/kg. In some embodiments, the subject can be dosed with the BCMA binding molecule with about 50 pg/kg. In some embodiments, the subject can be dosed with the BCMA binding molecule with about 75 pg/kg. In some embodiments, the subject can be dosed with the BCMA binding molecule with about 100 pg/kg.
  • the subject can be dosed with the BCMA binding molecule with about 200 pg/kg. In some embodiments, the subject can be dosed with the BCMA binding molecule with about 300 pg/kg. In some embodiments, the subject can be dosed with the BCMA binding molecule with about 400 pg/kg. In some embodiments, the subject can be dosed with the BCMA binding molecule with about 500 pg/kg. In some embodiments, the subject can be dosed with the BCMA binding molecule with about 600 pg/kg. In some embodiments, the subject can be dosed with the BCMA binding molecule with about 700 pg/kg. In some embodiments, the subject can be dosed with the BCMA binding molecule with about 800 pg/kg. In some embodiments, the subject can be dosed with the BCMA binding molecule with about 900 pg/kg. In some embodiments, the subject can be dosed with the BCMA binding molecule with about 1000 pg/kg.
  • the subject can be dosed with the BCMA binding molecule at a dose of at least 25 pg/kg. In some embodiments, the subject can be dosed with the BCMA binding molecule at a dose of at least 30 pg/kg.
  • the subject can be adminstered the BCMA binding molecule at a dose of about 1 pg/kg to about 20 pg/kg. In some embodiments, the subject can be administered the BCMA binding molecule at a dose of about 20 pg/kg to about 40 pg/kg. In some embodiments, the subject can be administered the BCMA binding molecule at a dose of about 80 pg/kg to about 120 pg/kg. In some embodiments, the subject can be administered the BCMA binding molecule at a dose of about 150 pg/kg to about 250 pg/kg. In some embodiments, the subject can be administered the BCMA binding molecule at a dose of about 300 pg/kg to about 500 pg/kg.
  • the subject can be adminstered the BCMA binding molecule at a dose of about 0.25 pg/kg to about 1200 pg/kg, for example, in some embodiments, the subject can be dosed with the BCMA binding molecule with about 1 pg/kg to about 1000 pg/kg. In some embodiments, the subject can be administered the BCMA binding molecule at a dose of about 10 pg/kg to about 900 pg/kg. In some embodiments, the subject can be administered the BCMA binding molecule at a dose of about 20 pg/kg to about 800 pg/kg. In some embodiments, the subject can be administered the BCMA binding molecule at a dose of about 30 pg/kg to about 700 pg/kg.
  • the subject can be administered the BCMA binding molecule at a dose of about 50 pg/kg to about 600 pg/kg. In some embodiments, the subject can be administered the BCMA binding molecule at a dose of about 75 pg/kg to about 500 pg/kg. In some embodiments, the subject can be administered the BCMA binding molecule at a dose of about 100 pg/kg to about 400 pg/kg. In some embodiments, the subject can be administered the BCMA binding molecule at a dose of about 150 pg/kg to about 300 pg/kg. In some embodiments, the subject can be administered the BCMA binding molecule at a dose of about 200 pg/kg to about 250 pg/kg.
  • the subject can be dosed with the BCMA binding molecule at a dose of about 0.5 pg/kg to about 20 pg/kg. In one embodiment, the BCMA binding molecule is administered to the subject at a dose of about 0.5 pg/kg to 10 pg/kg. In one embodiment, the BCMA binding molecule is administered to the subject at a dose of about 1 pg/kg to 10 pg/kg. In one embodiment, the BCMA binding molecule is administered to the subject at a dose of about 5 pg/kg to 10 pg/kg. In one embodiment, the BCMA binding molecule is administered to the subject at a dose of about 1 pg/kg.
  • the BCMA binding molecule is administered to the subject at a dose of about 3 pg/kg. In one embodiment, the BCMA binding molecule is administered to the subject at a dose of about 6 pg/kg. In one embodiment, the BCMA binding molecule is administered to the subject at a dose of about 10 pg/kg. In one embodiment, the BCMA binding molecule is administered to the subject at a dose of about 10 pg/kg to 20 pg/kg. In one embodiment, the BCMA binding molecule is administered to the subject at a dose of about 10 pg/kg to 15 pg/kg. In one embodiment, the BCMA binding molecule is administered to the subject at a dose of about 12 pg/kg.
  • the BCMA binding molecule is administered to the subject at a dose of about 100 pg/kg. In one embodiment, the BCMA binding molecule is administered to the subject at a dose of about 100 pg/kg to about 200 pg/kg. In one embodiment, the BCMA binding molecule is administered to the subject at a dose of about 150 pg/kg to about 200 pg/kg. In one embodiment, the BCMA binding molecule is administered to the subject at a dose of about 192 pg/kg. In one embodiment, the BCMA binding molecule is administered to the subject at a dose of about 150 pg/kg to about 250 pg/kg.
  • any of the dosing amounts disclosed throughout this disclosure can be used to dose the BCMA binding molecule, e.g., as a first or subsequent treatment dose.
  • a treatment dose can be about 1 pg/kg to about 1200 pg/kg or about 50 pg to about 96 mg. In another embodiment, a treatment dose can be about 3 pg/kg to about 600 pg/kg or about 150 pg to about 48 mg. In another embodiment, a treatment dose can be about 5 pg/kg to about 100 pg/kg or about 150 pg to about 8 mg. In another embodiment, a treatment dose can be about 10 pg/kg to about 200 pg/kg or about 500 pg to about 16 mg. In another embodiment, a treatment dose can be about 50 pg/kg to about 400 pg/kg or about 2.5 mg to about 32 mg.
  • a treatment dose can be about 24 pg/kg or about 1 .2 mg to about 1 .92 mg. In another embodiment, a treatment dose can be about 48 pg/kg or about 2.4 mg to about 3.84 mg. In another embodiment, a treatment dose can be about 96 pg/kg or about 4.8 mg to about 7.68 mg. In another embodiment, a treatment dose can be about 192 pg/kg or about 9.6 mg to about 15.36 mg. In another embodiment, a treatment dose can be about 384 pg/kg or about 19.2 mg to about 30.72 mg. In another embodiment, a treatment dose can be about 600 pg/kg or about 30 mg to about 48 mg.
  • a priming dose is needed or used.
  • the priming dose can be any of the doses described herein, and in some embodiments is lower than the first treatment dose.
  • the priming dose can be administered at any dose lower than 30 pg/kg.
  • the priming dose can be administered at a dose lower than 30 pg/kg, for example lower than 29 pg/kg, e.g., 10 pg/kg or 1 pg/kg.
  • the priming dose ranges about 0.5 pg/kg to about 6 pg/kg or about 25 pg to about 480 pg. In another embodiment, the priming dose is about 1 pg/kg or about 50 pg to about 80 pg. In another embodiment, the priming dose is about 2 pg/kg or about 100 pg to about 160 pg. In another embodiment, the priming dose is about 3 pg/kg or about 150 pg to about 240 pg. In another embodiment, the priming dose is about 4 pg/kg or about 200 pg to about 320 pg. In another embodiment, the priming dose is about 5 pg/kg or about 250 pg to about 400 pg. In another embodiment, the priming dose is about 6 pg/kg or about 300 pg to about 480 pg.
  • the infusion can occur over a span of about 3.5 hours. In some embodiments, the infusion can occur over a span of about 4 hours. In some embodiments, the infusion can occur over a span of about 4.5 hours. In some embodiments, the infusion can occur over a span of about 5 hours. In some embodiments, the infusion can occur over a span of about 5.5 hours. In some embodiments, the infusion can occur over a span of about 6 hours.
  • the infusion can occur over a span of about 30 minutes to about 1 hour. In some embodiments, the infusion can occur over a span of about 1 hour to about 2 hours. In some embodiments, the infusion can occur over a span of about 2 hours to about 3 hours. In some embodiments, the infusion can occur over a span of about 3 hours to about 4 hours. In some embodiments, the infusion can occur over a span of about 4 hours to about 5 hours. In some embodiments, the infusion can occur over a span of about 5 hours to about 6 hours. In some embodiments, the infusion can occur over a span of about 30 minutes to about 6 hours. In some embodiments, the infusion can occur over a span of about 1 hour to about 5 hours. In some embodiments, the infusion can occur over a span of about 1 .5 hours to about 4 hours. In some embodiments, the infusion can occur over a span of about 2 hours to about 3 hours.
  • any of the dosing time disclosed throughout can be used to dose the BCMA binding molecule and/or any of the other therapeutic agents disclosed throughout.
  • the BCMA binding molecule can be dosed once a week per dosing cycle. In some embodiments, the BCMA binding molecule can be dosed twice a week per dosing cycle. In some embodiments, the BCMA binding molecule can be dosed once every two weeks per dosing cycle.
  • the BCMA binding molecule can be dosed a single time per dosing cycle. In some embodiments, the BCMA molecule can be dosed twice per dosing cycle. In some embodiments, the BCMA binding molecule can be dosed three times per dosing cycle. In some embodiments, the BCMA binding molecule can be dosed four times per dosing cycle.
  • the BCMA binding molecule can also be administered to the subject one or more times over the course of time.
  • the BCMA binding molecule can be administered to the subject, once a week for four weeks.
  • the priming dose of the BMCA binding molecule can be administered prior to a first treatment dose at any time before the treatment dose is given.
  • the priming dose can be administered once a week before the first treatment dose is given.
  • the priming dose can be administered twice within one week before the first treatment dose is given.
  • one third of a priming dose is administered to the subject on day 1 of a course of treatment, with the remainder of the priming dose administered on day 2 of the treatment.
  • a first treatment dose is subsequently administered to the subject one of days 5-11 of the treatment (e.g., one of days 6-10, one of days 7-9 or day 8), a second treatment dose is subsequently administered to the subject one of days 12-18 of the treatment (e.g., one of days 13-17, one of days 14-16, or day 15), and a third treatment dose is subsequently administered to the subject one of days 19-25 (e.g., one of days 20-24, one of days 21 -23, or day 22) of the treatment.
  • days 5-11 of the treatment e.g., one of days 6-10, one of days 7-9 or day 8
  • a second treatment dose is subsequently administered to the subject one of days 12-18 of the treatment (e.g., one of days 13-17, one of days 14-16, or day 15)
  • a third treatment dose is subsequently administered to the subject one of days 19-25 (e.g., one of days 20-24, one of days 21 -23, or day 22) of the treatment.
  • GSi can be used for the prevention and/or treatment of cancer (e.g., a blood cancer such as multiple myeloma). In some embodiments, the GSi can be used to enhance the effect of a therapeutic agent. In some embodiments, the GSi can be used alone.
  • cancer e.g., a blood cancer such as multiple myeloma
  • the GSi can be used to enhance the effect of a therapeutic agent. In some embodiments, the GSi can be used alone.
  • the GSi doses can be admininstered in various forms, such as those suitible for oral dosing, such as in capsule form and liquid form.
  • the GSi is LY-450139, PF-5212362, BMS-708163, MK-0752, ELN-318463, BMS-299897, LY-411575, DAPT, AL-101 (BMS-906024), AL-102 (BMS-986115), PF-3084014, RO4929097, LY3039478, or any combination thereof.
  • the preferred GSi is AL-102 also know as BMS-986115.
  • the GSi is administered at a dose of about 0.1 mg to about 10 mg. In some embodiments, the GSi is administered at a dose of about 0.5 mg to about 9 mg. In some embodiments, the GSi is administered at a dose of about 0.75 mg to about 8 mg. In some embodiments, the GSi is administered at a dose of about 0.9 mg to about 7 mg. In some embodiments, the GSi is administered at a dose of about 1 mg to about 6 mg. In some embodiments, the GSi is administered at a dose of about 2 mg to about 5 mg. In some embodiments, the GSi is administered at a dose of about 3 mg to about 4 mg.
  • the GSi is administered at a dose of about 0.75 mg to about 5 mg. In some embodiments, the GSi is administered at a dose of about 0.8 mg to about 4 mg. In some embodiments, the GSi is administered at a dose of about 0.9 mg to about 3 mg.
  • the GSi is administered at a dose of about 0.9 mg. In some embodiments, the GSi is administered at a dose of about 1 mg. In some embodiments, the GSi is administered at a dose of about 2 mg. In some embodiments, the GSi is administered at a dose of about 3 mg. In some embodiments, the GSi is adminstered at a dose of about 4 mg. In some embodiments, the GSi is administered at a dose of about 5 mg. In some embodiments, the GSi is administered at a dose of about 6 mg. In some embodiments, the GSi is administered at a dose of about 7 mg. In some embodiments, the GSi is administered at a dose of about 8 mg. In some embodiments, the GSi is administered at a dose of about 9 mg.
  • the GSi is administered at a dose of about 10 mg.
  • the GSi is adminstered to the subject via an oral route, such as in the form of a capsule or liquid.
  • the single dosage can be however divided up into several doses.
  • 2 or more capsules can be given to the subject over the course of a single adminstration.
  • 1 capsule can be adminstered to the subject and then in a specified time later (e.g., 10 seconds, 30 seconds, 1 minutes, 5 minutes) an additional capsule can be adminstered to the subject.
  • a GSi can be adminstered before any such BCMA binding molecule is administered.
  • the GSi can be administered only before the BCMA molecule is adminstered.
  • the GSi can be administered only concurrently with BCMA molecule.
  • the GSi can be administered only after the BCMA molecule is adminstered.
  • more than one dose of the GSi can be administered in any given dosing cycle.
  • Two of more doses of GSi and one or more dose of a BCMA binding molecule can be adminstered in any given dosing cycle.
  • the first GSi dose is administered to the subject one day before the BCMA binding molecule is adminstered.
  • the second GSi dose is administered to the subject on the same day as the BCMA binding molecule.
  • the first GSi dose is administered to the subject the day before the BCMA binding molecule is administered and the second GSi dose is administered to the subject on the next day along with the BCMA binding molecule.
  • the second GSi dose is administered to the subject about 2 hours prior to the administration of the BCMA binding molecule. 8.3. Side Effect Reducing Agents
  • side effect reducing agents the agents and doses as described throughout the disclosure can be used in the manner as described throughout the disclosure. Further, these side effect reducing agents can be used as they are known to be safe and effective. Specific side effect reducing agents are disclosed throughout but can also include and are not limited to paracetamol, acetaminophen, antihistamines (e.g., diphenhydramine), steroids (e.g., glucocorticoids, e.g., prednisone, cortisone, dexamethasone), anti-T cell directed therapy (e.g., tocilizumab or canakinumab), antidiarrehals (e.g., loperamide), octreotide, emollients, antibiotics, or any combination thereof.
  • antihistamines e.g., diphenhydramine
  • steroids e.g., glucocorticoids, e.g., prednisone, cortisone, dexamethasone
  • the disclosure provides a method for treating subjects that have undergone treatment for a disease associated with expression of BCMA, comprising administering to the subject an effective amount of: (i) a BCMA binding molecule, and (ii) a GSI.
  • the GSI is AL-102.
  • the structure of AL-102 is shown below:
  • the first GSi dose is administered to the subject one day before the BCMA binding molecule is adminstered.
  • the second GSi dose is administered to the subject on the same day as the BCMA binding molecule.
  • the first GSi dose is administered to the subject the day before the BCMA binding molecule is administered and the second GSi dose is administered to the subject on the next day along with the BCMA binding molecule.
  • the second GSi dose is administered to the subject about 2 hours prior to the administration of the BCMA binding molecule.
  • a BCMA binding molecule (e.g., a BCMA bispecific antibody) is administered to the subject at a dose of about 6 pg/kg and a first and/or second GSi dose is administered to the subject at a dose of about 0.9 mg.
  • a BCMA binding molecule (e.g., a BCMA bispecific antibody) is administered to the subject at a dose of about 12 pg/kg and a first and/or second GSi dose is administered to the subject at a dose of about 0.9 mg.
  • a BCMA binding molecule (e.g., a BCMA bispecific antibody) is administered to the subject at a dose of about 48 pg/kg and a first and/or second GSi dose is administered to the subject at a dose of about 2 mg.
  • a BCMA binding molecule (e.g., a BCMA bispecific antibody) is administered to the subject at a dose of about 48 pg/kg and a first and/or second GSi dose is administered to the subject at a dose of about 4 mg.
  • each of the above BCMA binding molecule + GSi dosage regimens can be considered one cycle.
  • each cycle can continue until treatment is discontinued.
  • discontinuation of treatment can occur when the patient no longer responds to treatment, the negative side effects outweigh the benefit of treatment, the patient dies, the patient has a complete response, the patient has a partial response, the patient has stable disease, or any combination thereof.
  • the number of dosing cycles can be 2 cycles. In some embodiments, the number of dosing cycles can be 3 cycles. In some embodiments, the number of dosing cycles can be 4 cycles. In some embodiments, the number of dosing cycles can be 5 cycles. In some embodiments, the number of dosing cycles can be 6 cycles. In some embodiments, the number of dosing cycles can be 7 cycles. In some embodiments, the number of dosing cycles can be 8 cycles. In some embodiments, the number of dosing cycles can be 9 cycles. In some embodiments, the number of dosing cycles can be 10 cycles. In some embodiments, the number of dosing cycles can be 11 cycles.
  • the number of dosing cycles can be 12 cycles. In some embodiments, the number of dosing cycles can be 13 cycles. In some embodiments, the number of dosing cycles can be 14 cycles. In some embodiments, the number of dosing cycles can be 15 cycles. In some embodiments, the number of dosing cycles can be at least 16 cycles. In some embodiments, the number of dosing cycles can be at least 20 cycles. In some embodiments, the number of dosing cycles can be at least 25 cycles. In some embodiments, the number of dosing cycles can be at least 30 cycles. In some embodiments, the number of dosing cycles can be at least 35 cycles. In some embodiments, the number of dosing cycles can be at least 40 cycles. In some embodiments, the number of dosing cycles can be at least 45 cycles. In some embodiments, the number of dosing cycles can be at least 50 cycles. In some embodiments, the number of dosing cycles can be at least 52 cycles.
  • the disclosure provides a method for treating subjects having a B cell condition or disorder, comprising administering to the subject an effective amount of: (i) a BCMA binding molecule, and (ii) a gamma secretase modulator (e.g., a GSI).
  • a BCMA binding molecule e.g., a CDMA binding molecule
  • a gamma secretase modulator e.g., a GSI
  • a BCMA binding molecule and/or the GSi of the disclosure can be used in combination other known agents and therapies.
  • the BCMA binding molecules and/or the GSi can be used in treatment regimens in combination with surgery, chemotherapy, antibodies, radiation, peptide vaccines, steroids, cytoxins, proteasome inhibitors, immunomodulatory drugs (e.g., IMiDs), BH3 mimetics, cytokine therapies, stem cell transplant or any combination thereof.
  • an agent that is used in combination with a BCMA binding molecule and/or GSi is referred to herein as an “additional” agent.
  • each therapy can be administered to a subject at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic effect.
  • a BCMA binding molecule and/or GSi and one or more additional agents can be administered simultaneously, in the same or in separate compositions, or sequentially.
  • the BCMA binding molecule and/or GSi can be administered first, and the additional agent can be administered second, or the order of administration can be reversed.
  • the delivery of one treatment ends before the delivery of the other treatment begins.
  • the treatment is more effective because of combined administration.
  • the additional treatment is more effective, e.g., an equivalent effect is seen with less of the additional treatment, or the additional treatment reduces symptoms to a greater extent, than would be seen if the additional treatment were administered in the absence of the BCMA binding molecule and/or GSi treatment, or the analogous situation is seen with the BCMA binding molecule and/or GSi treatment.
  • delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other.
  • the effect of the combined treatments can be partially additive, wholly additive, or greater than additive.
  • the delivery can be such that an effect of the BCMA binding molecule and/or GSi treatment delivered is still detectable when the additional treatment is delivered.
  • the BCMA binding molecule and/or GSi and/or additional agents can be administered during periods of active disorder, or during a period of remission or less active disease.
  • a BCMA binding molecule and/or GSi can be administered before the treatment with the additional agent(s), concurrently with the treatment with the additional agent(s), post-treatment with the additional agent(s), or during remission of the disorder.
  • the BCMA binding molecule and/or GSi and/or the additional agent(s) can be administered in an amount or dose that is higher, lower or the same than the amount or dosage of each agent used individually, e.g., as a monotherapy.
  • the BCMA binding molecule when used in combination can be adminstered in an amount or dose that is lower than went used as a monotherapy.
  • the additional agent(s) of the combination therapies of the disclosure can be administered to a subject concurrently.
  • the term “concurrently” is not limited to the administration of therapies (e.g., prophylactic or therapeutic agents) at exactly the same time, but rather it is meant that a pharmaceutical composition comprising a BCMA binding molecule and/or GSi is administered to a subject in a sequence and within a time interval such that the molecules of the disclosure can act together with the additional therapy(ies) to provide an increased benefit than if they were administered otherwise.
  • each therapy can be administered to a subject at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect.
  • Each therapy can be administered to a subject separately, in any appropriate form and by any suitable route.
  • the BCMA binding molecule and/or GSi and the additional agent(s) can be administered to a subject by the same or different routes of administration.
  • the BCMA binding molecules and/or GSi and the additional agent(s) can be cyclically administered. Cycling therapy involves the administration of a first therapy (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by the administration of a second therapy (e.g., a second prophylactic or therapeutic agent) for a period of time, optionally, followed by the administration of a third therapy (e.g., prophylactic or therapeutic agent) for a period of time and so forth, and repeating this sequential administration, i.e., the cycle in order to reduce the development of resistance to one of the therapies, to avoid or reduce the side effects of one of the therapies (e.g., the BCMA binding molecule and/or GSi), and/or to improve the efficacy of the therapies.
  • the one or more additional therapeutic agents reduces a side effect of the GSi and/or the BCMA binding molecule.
  • the side effect is cytokine release syndrome (CRS).
  • the one or more additional therapeutic agents are other anticancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cyto protective agents, and combinations thereof.
  • the additional therapeutic agents can be antidiarrehals (e.g., loperamide), octreotide, glucocorticoids (e.g, prednisone, cortisone, dexamethasone), emollients, antibiotics, paracetamol, acetaminophen, antihistamines, anti-T cell directed therapy, or any combiniation thereof.
  • the additional therapeutic agent is a glucocorticoid.
  • the glucocorticoid can be dexamethasone or methylprednisolone.
  • glucocorticoid is dexamethasone and is administered at a dose of about 8 mg to about 10 mg daily.
  • the glucocorticoid is methylprednisolone and is administered at a dose of at least about 2 mg/kg.
  • the additional therapeutic agent is an anti-T cell directed therapy.
  • the anti-T cell directed therapy is tocilizumab, canakinumab, or any combination thereof.
  • the PD-1 inhibitor is PDR001 . In one embodiment, the PD-1 inhibitor is administered at a dose of about 100 mg once every four weeks, or about 200 mg once every four weeks, or about 300 mg once every four weeks, or about 400 mg once every four weeks, or about 500 mg once every four weeks. In one embodiment, the PD-1 inhibitor is administered at a dose of about 400 mg once every four weeks.
  • the additional therapeutic agent can be administered in any effective way.
  • the additional therapeutic agent can be administered orally.
  • the additional therapeutic agent can be administered intravenously.
  • the BCMA binding molecule and/or GSi and/or the one or more additional therapeutic agents can prevent or treat cancer.
  • the cancer is a blood cancer.
  • the blood cancer is multiple myeloma.
  • myeloma also known as plasma cell myeloma or Kahler’s disease
  • Kahler plasma cell myeloma
  • myeloma also known as plasma cell myeloma or Kahler’s disease
  • a cancer characterized by an accumulation of abnormal or malignant plasma B-cells in the bone marrow.
  • the cancer cells invade adjacent bone, destroying skeletal structures and resulting in bone pain and fractures.
  • Most cases of myeloma also feature the production of a paraprotein (also known as M proteins or myeloma proteins), which is an abnormal immunoglobulin produced in excess by the clonal proliferation of the malignant plasma cells.
  • Blood serum paraprotein levels of more than 30g/L is diagnostic of multiple myeloma, according to the diagnostic criteria of the International Myeloma Working Group (IMWG) (See Kyle et al., 2009, Leukemia. 23:3-9).
  • IMWG International Myeloma Working Group
  • Other symptoms or signs of multiple myeloma include reduced kidney function or renal failure, bone lesions, anemia, hypercalcemia, and neurological symptoms.
  • the BCMA binding molecules and/or GSi can be used to treat subjects in need thereof.
  • the subjects can be diagnosed with cancer, e.g., a blood cancer such as multiple myeloma.
  • a blood cancer such as multiple myeloma.
  • the subject has relapsed and/or refractory multiple myeloma.
  • the subject has been previously been treated for cancer.
  • the subjects can have previously been treated with one or more therapeutic agents.
  • the treatment may have failed.
  • the subject has previously received one or more prior treatments for their disease. In some embodiments, the subject has previously received one prior treatment for their disease. In some embodiments, the subject has previously received two prior treatments for their disease. In some embodiments, the subject has previously received three prior treatmenst for their disease. In some embodiments, the subject has previously received four or more prior treatments fortheir disease.
  • the prior treatment regimens did not comprise a multispecific antibody (e.g., a BCMA targeting multispecific antibody). In one embodiment, the prior treatment regimens did not comprise a CAR-T (e.g., a BCMA targeting CAR-T). In one embodiment, the prior treatment regimens did not comprise a RLT (e.g., a BCMA targeting RLT).
  • a multispecific antibody e.g., a BCMA targeting multispecific antibody
  • the prior treatment regimens did not comprise a CAR-T (e.g., a BCMA targeting CAR-T). In one embodiment, the prior treatment regimens did not comprise a RLT (e.g., a BCMA targeting RLT).
  • the subject that is treated with the BCMA binding molecule is not eligible for treatment with other anti-cancer regimens known to provide clinical benefit.
  • the subject that can be treated with the BCMA binding molecules and/or GSi can include a subject that has signed an informed consent form prior to being treated with the BCMA binding molecule and/or GSi.
  • the subject that can be treated with the BCMA binding molecules and/or GSi can include a subject that is a male or female subject that is greater than equal to 18 years of age.
  • the subject that can be treated with the BCMA binding molecules and/or GSi can include a subject that has a confirmed diagnosis of cancer.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can be a subject that has a confirmed diagnosis of multiple myeloma.
  • the subject can also have received two or more standard of care (SoC) regimens.
  • SoC regimens can include an IMiD (e.g. lenalidomide or pomalidomide), a proteasome inhibitor (e.g. bortezomib, carfilzomib), and/or an anti-CD38 agent (e.g. daratumumab.
  • the subject can also be relapsed and/or refractory to, or intolerant of each regimen.
  • the subject can also have documented evidence of disease progression (IMWG criteria) even after receiving previous treatments.
  • the subject can have also previously received a prior autologous bone marrow transplant, a BCMA CAR-T or BCMA-ADC.
  • the subject that can be treated with the BCMA binding molecules and/or GSi can include a subject that has a measureable diseased defined by serum M-protein level of greater than equal to 1 .0 g/dL.
  • the subject that can be treated with the BCMA binding molecules and/or GSi can include a subject that has a measureable diseased defined by urine M-protein level of greater than equal to 200 mg/24 hours.
  • the subject that can be treated with the BCMA binding molecules and/or GSi can include a subject that has a measureable diseased defined by serum free light chain (sFLC) of greater than 100 mg/L of involved FLC.
  • sFLC serum free
  • the subject that can be treated with the BCMA binding molecules and/or GSi can include a subject that is willing to undergo a serial bone marrow aspirate and/or biopsy.
  • the serial bone marrow aspirate and/or biopsy can occur at any time prior to treatment with the BCMA binding molecule and/or GSi.
  • the serial bone marrow aspirate and/or biopsy can occur at any time following treatment with the BCMA binding molecule and/or GSi.
  • the serial bone marrow aspirate and/or biopsy can be performed for the assessment of disease status and biomarker/pharmacodynamics.
  • the subject that can be treated with the BCMA binding molecules and/or GSi can include a subject that may not be using steroid therapy.
  • the steroid can be prednisone, dexamethasone, cortisol, equivalents thereof, or any other corticosteroids for human use.
  • the steroid therapy should not be chronic steroid therapy. For example, daily use of greater than equal to 10 mg of prednisone or equivalents can be considered chronic steroid therapy.
  • the steroids are topical, inhaled, nasal, or ophthalmic.
  • the subject can be eligible for the treatment with the BCMA binding molecule and/or GSi.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that may not have used any BCMAxCD3 bispecific antibody therapies in the past.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that does not have any malignant disease except for the disease that is being treated with the BCMA binding molecule and/or GSi.
  • the subject can include a subject that does not have two or more malignant diseases, one of which is not being treated by the BCMA binding molecule and/or GSi.
  • the malignancy has not recurred within the past five years. In some embodiments, the malignancy has not recurred within the past four years. In some embodiments, the malignancy has not recurred within the past three years. In some embodiments, the malignancy has not recurred within the past two years. In some embodiments, the malignancy has not recurred within the past year. In some embodiments, the malignancy has not recurred within the past six months.
  • exceptions can include subjects who had completely resected basal cell and squamous cell skin cancers. Further exceptions can include completely resected carcinoma in situ of any type. Under these circumstances, the subject can receive treatment with the BCMA binding molecule and/or GSi.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that does not have active autoimmune disease.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that is not known to have an autoimmune disease.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that is not suspected to have an autoimmune disease.
  • autoimmune diseases can be made for subjects have vitiligo, hypothyroidism, or psoriasis. If the subject has hypothyroidism, the subject can have residual hypothyroidism. In some embodiments, if the subject has residual hypothyroidism, the subject that can be treated with the BCMA binding molecule and/or GSi only requires hormone replacement. If the subject has psoriasis, the subject that can be treated with the BCMA binding molecule and/or GSi does not require systemic treatment. In some embodiments, if the subject has psoriasis, the condition is not expected to recur. Under these circumstances, the subject can receive treatment with the BCMA binding molecule and/or GSi.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that has not been treated with a prohibited medication.
  • the subject has not been treated with a prohibited medication that cannot be discontinued at least three months prior to the start of treatment.
  • the subject has not been treated with a prohibited medication that cannot be discontinued at least two months prior to the start of treatment.
  • the subject has not been treated with a prohibited medication that cannot be discontinued at least one month prior to the start of treatment.
  • the subject has not been treated with a prohibited medication that cannot be discontinued at least four weeks prior to the start of treatment.
  • the subject has not been treated with a prohibited medication that cannot be discontinued at least three weeks prior to the start of treatment.
  • the subject has not been treated with a prohibited medication that cannot be discontinued at least two weeks prior to the start of treatment. In some embodiments, the subject has not been treated with a prohibited medication that cannot be discontinued at least one week prior to the start of treatment. In some embodiments, the subject has not been treated with a prohibited medication that cannot be discontinued at least six days prior to the start of treatment. In some embodiments, the subject has not been treated with a prohibited medication that cannot be discontinued at least five days prior to the start of treatment. In some embodiments, the subject has not been treated with a prohibited medication that cannot be discontinued at least four days prior to the start of treatment. In some embodiments, the subject has not been treated with a prohibited medication that cannot be discontinued at least three days prior to the start of treatment. In some embodiments, the subject has not been treated with a prohibited medication that cannot be discontinued at least two days prior to the start of treatment. In some embodiments, the subject has not been treated with a prohibited medication that cannot be discontinued at least one day prior to the start of treatment.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that does not have greater than equal to grade 2 neuropathy.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that does not have greater than or equal to grade 1 residual toxic effects from any previous therapy.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that does not have plasma cell leukemia and other plasmacytoid disorders, other than multiple myeloma.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that does not have a clinical laboratory result of an absolute neutrophil count (ANC) of greater than 1 ,000/mm3 without growth factor support.
  • This ANC count can be measured 1 month prior to the start of treatment.
  • the ANC count can be measured 4 weeks prior to the start of treatment.
  • the ANC count can be measured 3 weeks prior to the start of treatment.
  • the ANC count can be measured 2 weeks prior to the start of treatment.
  • the ANC count can be measured 1 week prior to the start of treatment.
  • the ANC count can be measured 6 days prior to the start of treatment.
  • the ANC count can be measured 5 days prior to the start of treatment. In some embodiments, the ANC count can be measured 4 days prior to the start of treatment. In some embodiments, the ANC count can be measured 3 days prior to the start of treatment. In some embodiments, the ANC count can be measured 2 days prior to the start of treatment. In some embodiments, the ANC count can be measured 1 day prior to the start of treatment.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that does not have a clinical laboratory result of a platelet count less than 75,000 mm3 without transfusion support.
  • This platelet count can be measured 1 month prior to the start of treatment. In some embodiments, the platelet count can be measured 4 weeks prior to the start of treatment. In some embodiments, the platelet count can be measured 3 weeks prior to the start of treatment. In some embodiments, the platelet count can be measured 2 weeks prior to the start of treatment. In some embodiments, the platelet count can be measured 1 week prior to the start of treatment. In some embodiments, the platelet count can be measured 6 days prior to the start of treatment.
  • the platelet count can be measured 5 days prior to the start of treatment. In some embodiments, the platelet count can be measured 4 days prior to the start of treatment. In some embodiments, the platelet count can be measured 3 days prior to the start of treatment. In some embodiments, the platelet count can be measured 2 days prior to the start of treatment. In some embodiments, the platelet count can be measured 1 day prior to the start of treatment.
  • the bilirubin level can be greater than 1.7 times the ULN. In some embodiments, the bilirubin level can be greater than 1 .8 times the ULN. In some embodiments, the bilirubin level can be greater than 1.9 times the ULN. In some embodiments, the bilirubin level can be greater than 2.0 times the ULN.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that does not have a clinical laboratory result of an alanine aminotransferase (ALT) level that is greater than 3 times the upper limit of the normal range (ULN).
  • the ALT level can be greater than 1 .5 times the ULN.
  • the ALT level can be greater than 2.0 times the ULN.
  • the ALT level can be greater than 2.5 times the ULN.
  • the ALT level can be greater than 3.5 times the ULN.
  • the AST level can be greater than 4.0 times the ULN.
  • the ALT level can be greater than 4.5 times the ULN.
  • the ALT level can be greater than 5.0 times the ULN.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that does not have a clinical laboratory result of a calculated creatinine clearance less than 30 ml/min. In some embodiments, the calculated creatinine clearance less than 10 ml/min. In some embodiments, the calculated creatinine clearance less than 20 ml/min. In some embodiments, the calculated creatinine clearance less than 40 ml/min. In some embodiments, the calculated creatinine clearance less than 50 ml/min.
  • the calculated creatinine clearance can be measured by any known method. For example, the Cockcroft- Gault equation can be used to calculate creatinine clearance.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that does not have impaired cardiac function.
  • the subject that can be treated with the BCMA binding molecule and/or GSi does not have clinically significant cardiac disease.
  • the subject does not have clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (e.g., NYHA Grade > 2), uncontrolled hypertension or clinically significant arrhythmia.
  • the subject does not have a QTcF > 470 msec on screening ECG or congenital long QT syndrome.
  • the subject does not have acute myocardial infarction or unstable angina pectoris less than 3 months prior to treatment.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that does not have an active infection. In some embodiments, the subject does not have an active infection that requires systemic therapy. In some embodiments, the subject does not have any severe infection within one month before treatment. In some embodiments, the subject does not have any severe infection within four weeks before treatment. In some embodiments, the subject does not have any severe infection within three weeks before treatment. In some embodiments, the subject does not have any severe infection within two weeks before treatment. In some embodiments, the subject does not have any severe infection within one week before treatment.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that does not have human immunodeficiency virus (HIV infection).
  • HIV infection human immunodeficiency virus
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that has not been treated with cytotoxic or small molecule targeted antineoplastics or any experimental therapy before treatment. In some embodiments, the subject has not been treated with the cytotoxic or small molecule targeted antineoplastics or any experimental therapy within 1 month prior to commencing treatment with the BCMA binding molecule and/or GSi. In some embodiments, the subject has not been treated with the cytotoxic or small molecule targeted antineoplastics or any experimental therapy within 4 weeks prior to commencing treatment with the BCMA binding molecule and/or GSi.
  • the subject has not been treated with the cytotoxic or small molecule targeted antineoplastics or any experimental therapy within 10 half-lives prior to commencing treatment with the BCMA binding molecule and/or GSi. In some embodiments, the subject has not been treated with the cytotoxic or small molecule targeted antineoplastics or any experimental therapy within 7 half-lives prior to commencing treatment with the BCMA binding molecule and/or GSi. In some embodiments, the subject has not been treated with the cytotoxic or small molecule targeted antineoplastics or any experimental therapy within 5 half-lives prior to commencing treatment with the BCMA binding molecule and/or GSi.
  • the subject has not been treated with the cytotoxic or small molecule targeted antineoplastics or any experimental therapy within 4 halflives prior to commencing treatment with the BCMA binding molecule and/or GSi. In some embodiments, the subject has not been treated with the cytotoxic or small molecule targeted antineoplastics or any experimental therapy within 3 half-lives prior to commencing treatment with the BCMA binding molecule and/or GSi. In some embodiments, the subject has not been treated with the cytotoxic or small molecule targeted antineoplastics or any experimental therapy within 2 half-lives prior to commencing treatment with the BCMA binding molecule and/or GSi.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that has not had the initiation of hematopoietic colony-stimulating growth factors (e.g. G-CSF, M-CSF), thrombopoietin mimetics or erythroid stimulating agents less than or equal to two weeks prior to start of treatment.
  • the initiation did not occur less than one month prior to the start of treatment.
  • the initiation did not occur less than four weeks prior to the start of treatment.
  • the initiation did not occur less than three weeks prior to the start of treatment.
  • the initiation did not occur less than one week prior to the start of treatment.
  • the subject that can be treated with the BCMA binding molecule and/or GSis and/or GSi can include a subject that has not received GM-CSF.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that has not received intravenous IG infusions that were given for infection prophylaxis.
  • the IG infusions should have ended 3 months prior to the start of treatment with the BCMA binding molecule and/or GSi.
  • the IG infusions should have ended 2 months prior to the start of treatment with the BCMA binding molecule and/or GSi.
  • the IG infusions should have ended 1 month prior to the start of treatment with the BCMA binding molecule and/or GSi.
  • the IG infusions should have ended 4 weeks prior to the start of treatment with the BCMA binding molecule and/or GSi.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that does that have active central nervous system (CNS) involvement by malignancy or presence of symptomatic CNS metastases, or CNS metastases that require local CNS- directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids within 2 weeks prior to the start of treatment.
  • CNS issues should not have occurred 3 months prior to the start of treatment.
  • the CNS issues should not have occurred 2 months prior to the start of treatment.
  • the CNS issues should not have occurred 1 month prior to the start of treatment.
  • the CNS issues should not have occurred 4 weeks prior to the start of treatment.
  • the CNS issues should not have occurred 3 weeks prior to the start of treatment.
  • the CNS issues should not have occurred 1 week prior to the start of treatment.
  • the subject that can be treated with the BCMA binding molecule and/or GSi can include a subject that is not pregnant or nursing (lactating). Pregnancy can be defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
  • the subject that can be treated with the BCMA binding molecule and/or GSi is, in some embodiments, not a woman of child-bearing potential, unless they are using effective methods of contraception (e.g., two) during dosing and for 6 months after the last dose of study drug, including one highly effective method.
  • a woman of child-bearing potential can be defined as all women physiologically capable of becoming pregnant. Women can be considered postmenopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e.
  • Highly effective contraception methods include but are not limited to total abstinence, female sterilization, male sterilization, and use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), and other forms of hormonal contraception that have comparable efficacy (failure rate ⁇ 1%) (e.g., hormone vaginal ring or transdermal hormone contraception).
  • Other effective method of contraception include barrier methods of contraception such as condom or occlusive cap (diaphragm or cervical/vault caps) with spermicide, (e.g., foam, gel, film, cream, or vaginal suppository).
  • periodic abstinence e.g., calendar, ovulation, symptothermal, post-ovulation methods
  • withdrawal are not acceptable methods of contraception.
  • examples include but are not limited to surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
  • women must have been stable on the same pill for a minimum of three months before the commencement of treatment with the BCMA binding molecule and/or GSi.
  • BSBM3 a bispecific antibody that specifically binds to BCMA and CD3, as described in throughout the disclosure
  • AL-102 in subjects with multiple myeloma who have received two or more standard of care (SoC) lines of therapy including an I MiD (e.g. lenalidomide or pomalidomide), a proteasome inhibitor (e.g. bortezomib, carfilzomib), and an anti-CD38 agent (e.g.
  • I MiD e.g. lenalidomide or pomalidomide
  • proteasome inhibitor e.g. bortezomib, carfilzomib
  • an anti-CD38 agent e.g.
  • daratumumab are relapsed and/or refractory to or intolerant of each regimen, with documented evidence of disease progression per International Myeloma Working Group (IMWG) criteria and must not be eligible for treatment with other regimens known to provide clinical benefit, as determined by the investigator.
  • IMWG International Myeloma Working Group
  • BSBM3 as a single agent will be initially administered on a weekly (Q1W) schedule.
  • BSBM3 in combination will also be initially administered on a weekly (Q1 W) schedule with AL- 102 being administered weekly on a 2-days on 5-days off schedule.
  • Study drug treatment will continue until a subject experiences unacceptable toxicity, progressive disease as per IMWG or treatment is discontinued at the discretion of the investigator or the patient.
  • the study design is summarized in FIG. 6.
  • Alternative dosing schedules fpr BSBM3 (e.g. Q2W, Q3W, TIW) or AL- 102 may be implemented during the study if supported by emerging data including preliminary PK, PD and efficacy findings from this ongoing trial. If clinically significant cytokine release syndrome (CRS) or associated symptoms are observed during dose escalation, the option of a priming dose of BSBM3 may be introduced and subsequent dosing schedules modified.
  • CRS cytokine release syndrome
  • subjects with relapsed and/or refractory MM will be treated with single agent BSBM3 (Arm A) or BSBM3 in combination with AL-102 (Arm B) until the MTD/RD of each is reached.
  • BSBM3 single agent BSBM3
  • AL-102 Arm B
  • each arm it is estimated approximately 20 subjects are required during escalation to define the MTD/RD.
  • an additional enrichment cohort of 1- 6 patients with prior exposure to BCMA-directed therapies might be enrolled.
  • the safety (including the dose-DLT relationship) and tolerability of the study treatment will be assessed, and regimen(s) and dose(s) will be identified for use in the expansion part based on the review of these data.
  • MTD(s)/RD(s) have been determined in each escalation part, additional subjects will be enrolled in the expansion part in order to further characterize the PK, PD, and safety profile of study drug and to assess the preliminary anti-tumor activity of single agent BSBM3 or BSBM3 in combination of AL-102. More than one dose level at Q1W schedule might be explored as RDs for expansion. In addition, alternative dosing schedules may be explored in the escalation part. RD(s) of new schedules might be declared.
  • subjects with relapsed and/or refractory MM will be treated with single agent BSBM3 (Arm A) or BSBM3 in combination of AL-102 (Arm B).
  • the expansion part will enroll approximately 20 subjects. Enrollment may be halted early based on the ongoing review of data from the expansion cohort.
  • Newly obtained bone marrow aspirate and/or biopsy if available will be required to be submitted to a Novartis designated laboratory for biomarker assessment at screening/baseline for all subjects enrolled in dose escalation and dose expansion.
  • This study aims to start with safe doses of study treatment based on available pre- clinical data. Additionally, doses to be tested are expected to be in the range where anti-MM activity may be achieved.
  • Malignant disease other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type.
  • ILD interstitial lung disease
  • pneumonitis of grade > 2 Ongoing interstitial lung disease (ILD) or pneumonitis of grade > 2; or history of or ongoing ILD or pneumonitis of grade > 2
  • ILD interstitial lung disease
  • HIV infection Human immunodeficiency virus
  • HBV Active Hepatitis B
  • HCV Hepatitis C
  • thrombopoietin mimetics or erythroid stimulating agents were initiated more than 2 weeks prior to the first dose of study treatment and the patient is on a stable dose, they can be maintained. GM-CSF is not permitted due to the possible exacerbation of CRS.
  • BSBM3 and/or AL-102 are provided by Novartis.
  • BSBM3 is supplied as Liquid in vial (LI VI) formulation and it is composed of 10 mg/mL BSBM3, 20 mM histidine, 240 mM sucrose, PS20 0.04%, pH 5.5 ⁇ 0.3.
  • AL-102 is supplsed in a capsule.
  • subjects may not receive other additional investigational drugs, agents, devices, chemotherapy, or any other therapies that may be active against cancer. Additionally, no other therapeutic monoclonal antibodies and no immunosuppressive medication or live vaccines should be administered while on this study.
  • *lt is possible for additional and/or intermediate dose levels to be added during the course of the study. Cohorts may be added at any dose level below the MTD in order to better understand safety, PK or PD.
  • a priming dose will be used if, during dose escalation, 2 patients experience an event of Grade >3 infusion related reaction (IRR) or cytokine release syndrome (CRS), as defined in Section 12.11 .6 of the protocol, that does not resolve to Grade ⁇ 1 or baseline within 48 hours, and upon agreement between Novartis and Investigators if determined to be clinically necessary.
  • the priming dose will be selected at a dose level determined to be safe (the dose be at least one dose level lower than the maximum dose tested in the previous cohorts and meets the EWOC criteria).
  • one third of the priming dose will be given on Day 1 and two thirds of the dose on Day 2.
  • the “X +1/+2/+3” dose levels refer to 1/2/3 dose levels higher than X according to the provisional dose table.
  • *lt is possible for additional and/or intermediate dose levels to be added during the course of the study. Cohorts may be added at any dose level below the MTD in order to better understand safety, PK or PD.
  • Dose level -1 represents a treatment dose level to be implemented in case the starting dose level is not tolerated. No dose reduction below dose level -2 is permitted for this study.
  • the dose escalation is conducted in order to establish the dose(s) of single agent BSBM3 or BSBM3 in combination with AL-102 to be used in the expansion part. Specifically, it is the one or more doses that in the view of Investigators and Novartis study personnel have the most appropriate benefit-risk as assessed by the review of safety, tolerability, PK, any available efficacy, and PD, taking into consideration the maximum tolerated dose (MTD).
  • MTD maximum tolerated dose
  • Each dose escalation cohort in the single agent BSBM3 arm (Arm A) will start with 1 to 6 newly treated subjects. They must have adequate exposure and follow-up to be considered evaluable for dose escalation decisions (see Section 12.21.1 for criteria in the definition of the Dose Determining Set).
  • the minimum cohort size will be increased to three.
  • a staggered approach for the first two subjects in a cohort will be utilized. Following dosing of the first subject, the next subject will be dosed a minimum of 72 hours after the previous subject is dosed. Following completion of this staggered dosing of the first two subjects, subsequent subjects will be treated without staggering, however, no more than 1 patient within a cohort will have their first infusion on any given day. Dose escalation decisions will be made when all subjects in a cohort have completed the DLT evaluation period or discontinued.
  • any dose escalation decisions made by investigators and Novartis personnel will not exceed the dose level satisfying the EWOC principle by the Bayesian logistic regression model (BLRM).
  • the dose for the next escalation cohort will not exceed a 100% increase from the previously tested safe dose.
  • the combination dose escalation part, or BSBM3 and AL-102 will not be escalated at the same time. For example, if a decision is made to escalate BSBM3 in the combination, dose level of AL-102 will remain the same as previously tested dose combination. Smaller increases in dose may be recommended by the Investigators and Sponsor upon consideration of all of the available clinical data.
  • enrichment cohorts of 1 to 6 subjects may be enrolled at any dose level or dose combination at or below the highest dose or dose combination previously tested and shown to be safe.
  • Subjects with prior exposure to BCMA-directed therapies might be enrolled as a separate enrichment cohort of up to 6 subjects at the active combination dose.
  • the BLRM will be updated with the most up-to-date new information from all cohorts, without waiting for all subjects from the current cohort to complete the evaluation period.
  • the 2 DLTs occur in an enrichment cohort, then upon re-evaluation of all relevant data, additional subjects may be enrolled into the open cohorts only if the dose still meets the EWOC criteria. Alternatively, if recruitment to the same dose cannot continue, a new cohort of subjects may be recruited to a lower dose that satisfies the EWOC criteria. Additionally, if 2 or more patients experience a DLT in a dosing cohort, the next dose-escalation level will not be more than 50% above the previous dose level.
  • the current dose being tested may be de-escalated based on new safety findings, including but not limited to observing a DLT, before a cohort is completed. Subsequent to a decision to de-escalate, re-escalation may occur if data in subsequent cohorts supports this (EWOC criteria are satisfied).
  • the available toxicity information including adverse events and laboratory abnormalities that are not DLTs
  • the available PK and PD information will all be evaluated by the Investigators and Novartis study personnel (including the study physician and statistician) during a dose decision meeting by teleconference.
  • Drug administration at the next higher dose level may not proceed until the investigator receives written confirmation from Novartis indicating that the results of the previous dose level were evaluated and that it is permissible to proceed to a higher dose level.
  • Intra-subject dose escalation is not permitted at any time within the first 2 cycles of treatment. After the 2nd cycle is completed, individual subjects may be considered for treatment at a dose of single agent BSBM3 higher than the dose to which they were initially assigned.
  • the same guidelines apply to subjects receiving BSBM3 in combination with AL-102, with escalation of only one of the investigational drugs at any one time.
  • a subject In order for a subject to be treated at a higher dose of BSBM3 or BSBM3 in combination with AL-102, he or she must have tolerated the lower dose for at least 2 cycles of therapy (i.e. he or she must not have experienced any non-hematologic toxicity CTCAE grade > 2 at the lower dose originally assigned).
  • the new, higher dose with which the subject is to be treated must be a dose that has completed evaluation, and has shown to satisfy the EWOC principle at the last dose escalation teleconference before the time of the intra-subject escalation.
  • the following rules apply: The subject must have experienced no CTCAE grade > 2 toxicity over at least two cycles of therapy at the lower dose, and the higher dose being considered must have been fully evaluated and shown not to exceed the MTD. Consultation and agreement with Novartis must occur prior to any intra-subject dose escalation occurring. Data from the first cycle of treatment at the new dose level will not be formally included into the statistical model describing the relationship between dose and occurrence of DLT. However, this data will be incorporated into the clinical assessment of safety within a dose escalation teleconference.
  • DLTs dose limiting toxicities
  • a dose-limiting toxicity is defined as an adverse event or abnormal laboratory value where the relationship to single agent BSBM3 or BSBM3 in combination with AL-102 cannot be ruled out, and is not clearly related solely to disease progression or inter-current illness that occurs within the DLT evaluation period (Cycle 1 : C1 D1 ;C1 D28) with single agent BSBM3 or BSBM3 in combination with AL-102 and meets any of the criteria included in Table 4.
  • the National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 5.0 will be used for all grading. For the purpose of dose-escalation decisions, DLTs will be considered and included in the BLRM.
  • the investigator must notify the sponsor immediately of any unexpected CTCAE grade > 3 adverse events or laboratory abnormalities.
  • Colitis Grade 2 colitis is a DLT if it persists > 7 days despite treatment with corticosteroids.
  • eP at ' c Grade 2 ALT or AST accompanied by bilirubin >1 .5 x ULN is a DLT.
  • Dermatologic Grade 2 bullous disease that does not resolve to ⁇ Grade 1 within 7 days of starting corticosteroids is a DLT.
  • cycle 1 Other adverse events Other clinically significant toxicities in cycle 1 may be considered to be DLTs by the Investigators and Novartis, even if not CTCAE Grade 3 or higher.
  • a patient experiences an AE meeting the criteria for DLT as outlined in Section 12.11.3 including events occurring after cycle 1 , which is after the DLT period
  • treatment should be withheld.
  • the patient may resume study treatment at the same or a lower dose level assessed to be safe (or decreasing the dosing frequency) except as described below as pertaining to Grade 3 non-hematologic AEs, if there is no evidence of confirmed disease progression as per IMWG.
  • a decision to resume study treatment following the occurrence of a DLT is at the discretion of the Investigator.
  • BSBM3 For adverse events of potential immune-related etiology (irAE) that do not recover to ⁇ Grade 1 or baseline at a dose of immunosuppression of ⁇ 10 mg/day prednisone or equivalent within 12 weeks after initiation of immunosuppressive therapy, BSBM3 must be permanently discontinued.
  • study drug should be interrupted and not resumed until the event improves to Grade ⁇ 1 . At that point, the study drug may be resumed at the next lower dose level.
  • Monitor vital signs e.g. blood pressure, pulse, respiration, and temperature
  • CRS Cytokine Release Syndrome
  • Grade 2 or Grade 3 See instructions for Grade 2 and 3 Infusion Reaction above.
  • Grade 2 Hold study treatment if does not respond to topical therapy and doesn’t improved to grade 1 severity within 2 weeks of the initiation of local therapy or if requires systemic treatment Urgent ophthalmology consultation.
  • ⁇ Grade 1 Upon resolution to ⁇ Grade 1 may consider resuming study treatment without dose reduction after discussion with the Novartis Medical Monitor and in consultation with ophthalmology.
  • Baseline ECG refers to the ECG(s) collected at screening.
  • ⁇ Grade 1 or baseline may resume study treatment at a reduced dose after discussion with the Novartis Medical Monitor.
  • Grade 3 not associated with symptoms Continue study treatment. or clinical manifestations of If levels do not resolve to ⁇ Grade 2 within ⁇ 14 days after the initial pancreatitis** report, hold study treatment.
  • Grade 3 Hold treatment until returns to ⁇ Grade 1 or baseline and may restart at lower dose. If treatment delay >21 days, discontinue
  • Grade 3 May resume study treatment at a reduced dose upon resolution to ⁇ Grade 1 or baseline after discussion with the Novartis Medical Monitor
  • CRS Cytokine Release Syndrome
  • loperamide or other antidiarrheal treatment
  • atropine may be added or used instead of loperamide.
  • Additional antidiarrheal measures, such as octreotide, may be used at the discretion of the investigator or treating physician.
  • BSBM3 Upon resolution to ⁇ Grade 1 or baseline within 7 days, may resume BSBM3 and AL-102 at a reduced dose after discussion with the Novartis Medical Monitor. Dose reduction of AL-102 should be considered before changing the dose of BSBM3.
  • ⁇ Grade 1 Upon resolution to ⁇ Grade 1 , may resume BSBM3 and AL-102 without dose modification, if no clinical evidence of pancreatitis and after discussion with the Novartis Medical Monitor.
  • Grade 3 Hold both study drugs until returns to ⁇ Grade 1 or baseline and then restart both drugs with a dose reduction to one dose level below. If treatment delay >21 days, permanently discontinue study treatment.
  • Baseline ECG refers to the ECG(s) collected at screening.
  • treatment delay is > 21 days, permanently discontinue BSBM3 and AL-102
  • Grade 4 Hold BSBM3 and AL-102. Check complete blood count at least twice weekly. Upon resolution to ⁇ Grade 2, restart BSBM3 and AL- 102 at one dose level below.
  • treatment delay is >21 days, permanently discontinue BSBM3 and AL-102
  • Grade 3 or Grade 4 Hold study BSBM3 and AL-102 until fever resolves then follow guidance for non-febrile neutropenia.
  • treatment delay is ⁇ 21 days, restart BSBM3 and AL-102 at one dose level below.
  • treatment delay is > 21 days, permanently discontinue BSBM3 and AL-102
  • treatment delay is > 21 days, permanently discontinue BSBM3 and AL-102
  • estart BSBM3 and AL-102 one dose level below.
  • Grade 3 or Grade 4 Treatment-related anemia does not require study treatment hold or discontinuation.
  • Treatment-related lymphopenia does not require study treatment hold or discontinuation.
  • hypokalemia and hypocalcemia not appropriately managed with electrolyte replacement, consider reducing AL-102 to one dose level below.
  • Grade 4 Isolated Grade 4 electrolyte abnormalities not associated with clinical sequelae and corrected after appropriate management within 72 hours of their onset, do not require discontinuation.
  • BSBM3 and AL-102 may be continued at same or lower dose after documented discussion with Novartis
  • CCAE Common Toxicity Criteria for Adverse Events
  • Immune-Related AE irAE
  • irAE Immune-Related AE
  • An irAE is any clinically significant adverse event affecting any organ that is associated with study drug exposure, is consistent with an immune-mediated mechanism, and where alternative explanations have been investigated and ruled out or are considered to be unlikely.
  • Serologic, histologic (tumor sample) and immunological assessments should be performed as deemed appropriate by the Investigator or specialist consultant to verify the immune-related nature of the AE.
  • An empiric trial of corticosteroids may also contribute to understanding the etiology of a potential irAE.
  • Subjects treated with BSBM3 alone or in combination may be at an increased risk of infusion reactions, cytokine release syndrome, neurotoxicity, immunosuppression and associated infections, immuno-inflammatory reactions, tumor lysis syndrome, gastrointestinal toxicity, and elevated liver enzymes.
  • treatment of adverse events should follow standard institutional practice. Additional guidance is provided below.
  • tocilizumab Ensure that at least 2 doses of tocilizumab per patient are available on site prior to infusion of BSBM3. Hospitals should have timely access to additional doses of tocilizumab. Supportive care, tocilizumab, and corticosteroids have been used for effective management of CRS. Prompt responses to tocilizumab have been seen in most subjects.
  • CRS cytokine release syndrome
  • a recommended treatment algorithm for the management of CRS is presented below in Table 7 and Table 8.
  • the CRS management algorithm is a guideline and the investigator may use discretion or modify the treatment approach as needed for an individual subject.
  • Cardiovascular Tachycardia widened pulse pressure, hypotension, increased cardiac output
  • Neurologic Headache mental status changes, confusion, delirium, word finding difficulty or frank aphasia, hallucinations, tremor, dysmetria, altered gait, seizures Table 7 CRS Management
  • anti-cytokine and anti-T-cell therapies may include siltuximab (11 mg/kg i.v. over 1 hour), high doses of steroids (e.g. high dose methylprednisolone or equivalent steroid dose according to local ICU practice) cyclophosphamide, anti-thymocyte globulin (ATG) or alemtuzumab.
  • steroids e.g. high dose methylprednisolone or equivalent steroid dose according to local ICU practice
  • ATG anti-thymocyte globulin
  • alemtuzumab alemtuzumab
  • anti-cytokine therapies may also be considered upon their availability, if the subject does not respond to tocilizumab. If the subject experiences ongoing CRS despite administration of anti-cytokine directed therapies, anti-T-cell therapies such as cyclophosphamide, anti-thymocyte globulin (ATG) or alemtuzumab may be considered. These therapies need to be captured in appropriate CRFs.
  • anti-T-cell therapies such as cyclophosphamide, anti-thymocyte globulin (ATG) or alemtuzumab may be considered. These therapies need to be captured in appropriate CRFs.
  • Neurologic events primarily reflective of encephalopathy and delirium, have been reported with CD3-engaging bispecific antibodies and may occur after BSBM3 infusion. These present clinically as signs and symptoms of varying severity including: confusion, disorientation, agitation, aphasia, somnolence and tremors. In severe cases seizures, motor weakness, incontinence, impaired consciousness, increased intracranial pressure, and cerebral edema may be concurrent to, following the resolution or in the absence of CRS. Subjects should be monitored for neurologic events, diagnostically worked-up and managed depending on the underlying pathophysiology and in accordance to local standard of care.
  • BSBM3 is contraindicated in subjects with known hypersensitivity to BSBM3 orto any component of the product formulation. If a subject experiences an infusion reaction and there is a concern for repeat toxicity during or after subsequent doses of BSBM3, in addition to providing maximum premedication, consider reducing the rate of infusion to 50% of the initial speed.
  • systemic antibiotic therapy should be considered and started when an infection is suspected as per local institutional guidelines for the treatment of infections in patients with MM. Institutional guidelines for vaccination (e.g. pneumococcus) should be followed before starting BSBM3 therapy alone and in combination. No live vaccines should be used in BSBM3 recipients or prospective recipients.
  • Institutional guidelines for vaccination e.g. pneumococcus
  • No live vaccines should be used in BSBM3 recipients or prospective recipients.
  • Inflammation may reflect rebound immuno-inflammatory reactions during immune reconstitution, raising the potential for worsening of multifocal systemic inflammation after cessation of therapy. Therefore, patients should be monitored for clinical or laboratory signs of immune reconstitution syndrome (i.e., symptoms associated with cytokine release syndrome or autoimmune sequelae) while on the study and during the 90 day post treatment follow-up period.
  • immune reconstitution syndrome i.e., symptoms associated with cytokine release syndrome or autoimmune sequelae
  • TLS Tumor lysis syndrome
  • Subjects should be closely monitored for signs and symptoms of TLS both before and after BSBM3 infusion including relevant laboratory tests. To minimize risk of TLS, subjects with elevated uric acid or high tumor burden should receive allopurinol, or an alternative prophylaxis, prior to BSBM3 infusion as indicated. Subjects diagnosed with TLS should be managed according to local guidelines.
  • Patients should be monitored for Gl toxicity and given appropriate supportive care and therapy for symptoms. If a patient has experienced BSBM3 or AL-102-related nausea, vomiting, and/or diarrhea, and it is considered sufficiently severe to warrant the use of prophylactic antiemetic therapy, then prophylactic therapy may be used in that patient with subsequent treatment. If diarrhea, nausea, vomiting, and/or abdominal pain are observed in patients on BSBM3 alone or in combination with AL-102, clinical evaluation should include a thorough work up of potential infectious etiologies, including systemic infections, prior to the administration of steroids for potential immune-mediated causes of diarrhea or other Gl toxicity.
  • Appropriate empiric antibiotic therapy should be considered and started when a localized or systemic infection of the Gl tract is suspected as per local institutional guidelines for the treatment of such infections in patients with MM.
  • treatment with loperamide should be initiated at the earliest onset of symptoms.
  • standard doses of atropine may be added or used instead of loperamide.
  • Additional antidiarrheal measures, such as octreotide, may be used at the discretion of the investigator or treating physician. Fluid intake should be increased as clinically appropriate. Parenteral hydration should be started if oral hydration is not sufficient.
  • dexamethasone 8 mg to 10 mg daily, followed by tapering over several days, may be considered if colitis is suspected, as in nonclinical models with other GSIs, co-administration of dexamethasone has been shown to decrease the severity of intestinal pathology (Real, 2009; Wei, 2010) .
  • treatment with both drugs should be interrupted to allow for appropriate diagnosis, treatment, and recovery. If Gl bleeding is considered related to AL-102, a dose reduction of AL-102 should be considered.
  • Study drug compliance will be assured by administrations of the study treatment under the supervision of investigator or his/ her designee. Also, it will be verified by determinations of BSBM3 or AL-102 in blood on the days that PK samples are collected.
  • the investigator or designee must maintain an accurate record of the drug receipt logs and Drug Accountability Forms. Drug accountability will be reviewed by the field monitor during site visits and prior to the completion of the study. At study close-out, and, as appropriate during the course of the study, the investigator will return a copy of the completed drug accountability forms to the Novartis monitor or to the Novartis address provided in the investigator folder at each site.
  • Eligible subjects may only be included in the study after providing (witnessed, where required by law or regulation), IRB/IEC-approved informed consent.
  • the subject in cases where the subject's representative(s) gives consent (if allowed according to local requirements), the subject must be informed about the study to the extent possible given his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by personally signing and dating the written informed consent document.
  • Informed consent must be obtained before conducting any study-specific procedures (e.g. all of the procedures described in the protocol).
  • the process of obtaining informed consent must be documented in the subject source documents.
  • IB Information about common side effects already known about the investigational drug can be found in the Investigator's Brochure (IB). This information will be included in the subject informed consent and should be discussed with the subject during the study as needed. Any new information regarding the safety profile of the investigational drug that is identified between IB updates will be communicated as appropriate, for example, via an investigator notification or an aggregate safety finding. New information might require an update to the informed consent and then must be discussed with the subject. Women of child bearing potential must be informed that taking the study treatment may involve unknown risks to the fetus if pregnancy were to occur during the study and agree that in order to participate in the study they must adhere to the contraception requirements.
  • BSBM3 drug product is formulated for intravenous administration as 50 mg/5 ml liquid in vial (LIVI) concentrate for solution for infusion.
  • the dose for each administration for BSBM3 is based on the patient’s actual baseline weight measurement in kilograms on Day 1 (pre-dose). Following the first dose, subsequent doses will only be modified if the patient’s weight changes by more than 10% from the Day 1 weight, at which point it will be recalculated using the current weight.
  • AL-102 will be adminstered as a fixed dose and is provided as a 0.3 mg or 2.0 mg capsule.
  • a unique medication number is printed on the study medication label.
  • Medication labels will be in the local language and comply with the legal requirements of each country. They will include storage conditions for the study treatment but no information about the subject except for the medication number.
  • Study treatment must be received by a designated person at the study site, handled and stored safely and properly and kept in a secured location to which only the investigator and designated site personnel have access. Upon receipt, all study treatment must be stored according to the instructions specified on the labels and in the Investigator’s Brochure. Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints are to be reported to the respective Novartis CO Quality Assurance.
  • Medication labels will be in the local language and comply with the legal requirements of each country. They will include storage conditions for the study treatment but no information about the subject except for the medication number.
  • the investigator must maintain an accurate record of the shipment and dispensing of study treatment in a drug accountability log. Monitoring of drug accountability will be performed by monitors during site visits or remotely and at the completion of the trial.
  • the investigator will return all unused study treatment, packaging, drug labels, and a copy of the completed drug accountability log to the Novartis monitor or to the Novartis address provided in the investigator folder at each site.
  • the Assessment Schedules (Table 9) for subjects enrolled in Arm A, and (Table 9-2) for subjects enrolled in Arm B, lists all of the assessments when they are performed. All data obtained from these assessments must be supported in the subject’s source documentation.
  • Subjects should be seen for all visits/assessments as outlined in the assessment schedules (Table 9 or Table 9-2). A visit window of +/- 1 day is permitted to allow scheduling flexibility around holidays or other scheduling conflicts, unless otherwise noted in this protocol. Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who prematurely discontinue the study for any reason should be scheduled for a visit as soon as possible, at which time all of the assessments listed for the final visit will be performed. At this final visit, all dispensed investigational product should be reconciled, and the adverse event and concomitant medications recorded on the CRF.
  • the study IRB/IEC informed consent form must be signed and dated before any screening/baseline procedures are performed; laboratory and radiological assessments performed as part of standard of care prior to signing informed consent may be used if performed within the screening/baseline window.
  • a new ICF will need to be signed if the investigator chooses to re-screen the patient after a patient has screen failed, however, the patient ID number will remain the same. All required screening activities must be performed when the patient is re-screened for participation in the study. It is not necessary to repeat the bone marrow aspirate/core biopsy or CT/MRI if performed within 6 weeks of C1 D1 .
  • a patient who signed an Informed Consent Form but failed to be started on-treatment for any reason will be considered a screen failure.
  • the screening failure reason will be entered on the Screening Phase Disposition eCRF.
  • the demographic information, informed consent, and Inclusion/Exclusion pages must also be completed for Screen Failure subjects. No other data will be entered into the clinical database for subjects who are screen failures, unless the patient experienced a SAE during screening/baseline for SAE reporting details) or died (Death eCRF should be completed) or withdrew consent (Withdrawal of consent eCRF should be completed).
  • Data to be collected will include general patient demographics, relevant medical history and current medical conditions, diagnosis of multiple myeloma, details of prior anti-neoplastic treatments, prior medication, procedures, significant non-drug therapies and any other assessments that are done for the purpose of determining eligibility for inclusion in the study.
  • Disease classification at baseline and evaluation of response during study treatment rely on blood, urine, and bone marrow assessment, as well as on presence or absence of bony or extramedullary disease. See Table 9 and Table 9-2 for schedule of efficacy assessments. Disease response will be assessed by the Investigator as detailed in Table 9 and Table 9-2 and as per the International Uniform Response Criteria for MM by the International Myeloma Working Group and will need to be confirmed with two consecutive measurements.
  • a skeletal survey using X-ray, CT or MRI scanning must be performed to assess extent of bone disease at Screening (within 28 days prior to first dose of study drug on Day 1 of Cycle 1).
  • skeletal survey of affected areas should be performed at Cycle 3 Day 1 (Arm A) or Cycle 3 Day 2 (Arm B), ( ⁇ 3 days), subsequent cycles as clinically indicated, or to document a response of partial response (PR) or better, or to evaluate disease progression, and at end of treatment.
  • PR partial response
  • the same imaging modality should be used for post-baseline follow-up when possible.
  • a CT or MRI scan should be performed in subjects with known or suspected extramedullary disease at Screening (within 28 days prior to first dose of study drug on Day 1 of Cycle 1). See Table 9 and Table 9-2.
  • CT or MRI scans should be performed at Cycle 3 Day 1 , (Arm A) or Cycle 3 Day 2 (Arm B), ( ⁇ 3 days), subsequent cycles as clinically indicated, or to document a response of PR or better, or to evaluate disease progression, and at end of treatment.
  • the same imaging modality should be used for post-baseline follow-up when possible.
  • imaging with CT/MRI does not need to be performed.
  • Serum immunofixation must be measured at the following times and as clinically indicated:
  • Serum free light chain assay will be performed to assess the changes in the immunoglobulin free light chains at the following times and as clinically indicated:
  • Serum Immunoglobulin panel will be performed to assess immunoglobulin levels, and changes in the blood at the following times and as clinically indicated:
  • a bone marrow aspirate for plasma cell quantification will be collected at the following times and as clinically indicated:
  • Cycle 13 ( ⁇ 7 days) (including sample for biomarker assessment)
  • bone marrow aspirate sample A portion of the bone marrow aspirate sample is required to evaluate biomarkers. If bone marrow aspirate sample is not available or insufficient at screening, a newly obtained bone marrow core biopsy samples should be obtained, if feasible. Refer to the biomarker sample collection plan in for additional details.
  • Safety will be monitored by assessing physical exam, vital signs, weight, ECOG Performance Status, laboratory evaluations, and cardiac assessment, as well as collecting adverse events at every visit. All safety assessments will be reviewed and/or analyzed locally. ECGs will also be transmitted to a central laboratory and be centrally reviewed by an independent reviewer.

Abstract

La présente divulgation concerne des schémas posologiques, des formulations et des associations comprenant un anticorps multispécifique présentant au moins une spécificité de liaison vis-à-vis de l'antigène de maturation des lymphocytes B et un bras d'activation des lymphocytes T ; et des procédés d'utilisation de tels anticorps multispécifiques dans le traitement ou la prévention d'une maladie, telle que le cancer.
PCT/IB2021/060276 2020-11-05 2021-11-05 Schéma posologique et polythérapies avec des anticorps multispécifiques ciblant un antigène de maturation des lymphocytes b et des inhibiteurs de gamma secrétase WO2022097090A1 (fr)

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