US20160022813A1 - Compositions comprising anti-cd38 antibodies and carfilzomib - Google Patents

Compositions comprising anti-cd38 antibodies and carfilzomib Download PDF

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US20160022813A1
US20160022813A1 US14/775,641 US201414775641A US2016022813A1 US 20160022813 A1 US20160022813 A1 US 20160022813A1 US 201414775641 A US201414775641 A US 201414775641A US 2016022813 A1 US2016022813 A1 US 2016022813A1
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antibody
seq
carfilzomib
antibodies
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Blake Tomkinson
Blake T. Aftab
Byron C. Hann
Thomas G. Martin, III
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Sanofi SA
University of California San Diego UCSD
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Sanofi SA
University of California San Diego UCSD
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    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • 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
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    • 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
    • C—CHEMISTRY; METALLURGY
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    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
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    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
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    • C07—ORGANIC CHEMISTRY
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
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    • C07K2317/734—Complement-dependent cytotoxicity [CDC]

Definitions

  • the field of the present invention relates to anti-CD38 antibodies, carfilzomib, and cancer treatments.
  • MM Multiple myeloma
  • proteasome inhibitors such as bortezomib and carfilzomib
  • immunomodulatory drugs such as lenalidomide and thalidomide
  • chemotherapy such as melphalan and prednisone. While these agents have improved survival in multiple myeloma, invariably resistance becomes problematic and patients succumb from their illness. Multiple myeloma thus remains ultimately fatal, with a median survival of approximately 3 to 5 years only.
  • CD38 is expressed on malignant plasma cells.
  • CD38 is a 45 kD type II transmembrane glycolprotein with a long C-terminal extracellular domain and a short N-terminal cytoplasmic domain.
  • the CD38 protein is a bifunctional ectoenzyme that can catalyze the conversion of NAD + into cyclic ADP-ribose (cADPR) and also hydrolyze cADPR into ADP-ribose.
  • cADPR cyclic ADP-ribose
  • CD38 is up-regulated and has been implicated in many hematopoietic malignancies.
  • some proposed MM treatments include the administration of anti-CD38 antibodies. See, for example, WO 2012/041800; de Weers et al. (2011) J Immunol 186:1840-1848; and Van der Veer et al. (2011) Haematologica 96(2):284-290. Unfortunately, like various drugs and chemotherapies, not all antibodies are the same and not all antibodies against the same antigen exhibit the same activities.
  • FIG. 1A shows the growth rate of tumors in xenograft models implanted with NCI-H929 cells (H929 models).
  • FIG. 1B shows the growth rate of tumors in xenograft models implanted with RPMI 8226 cells (RPMI models).
  • FIG. 2A shows the tumor volume of tumors in RPMI models after treatment with the indicated dose of hu38SB19 at the indicated times (arrows).
  • FIG. 2B shows the body weight of the RPMI models after treatment with the indicated dose of hu38SB19 at the indicated times (arrows).
  • FIG. 3A shows the tumor volume of tumors in H929 models after treatment with the indicated dose of hu38SB19 at the indicated times (arrows).
  • FIG. 3B shows the body weight of the H929 models after treatment with the indicated dose of hu38SB19 at the indicated times (arrows).
  • FIG. 4A shows the tumor volume of tumors in H929 models after treatment with the indicated dose of hu38SB19 at the indicated times (arrows).
  • FIG. 4B shows the body weight of the H929 models after treatment with the indicated dose of hu38SB19 at the indicated times (arrows).
  • FIG. 5A shows the tumor volume of tumors in H929 models after treatment with the indicated dose of hu38SB19 at the indicated times (arrows).
  • FIG. 5B shows the body weight of the H929 models after treatment with the indicated dose of hu38SB19 at the indicated times (arrows).
  • FIG. 6A shows the tumor volume of tumors in H929 models after treatment with the indicated dose of carfilzomib at the indicated times (arrows).
  • FIG. 6B shows the body weight of the H929 models after treatment with the indicated dose of carfilzomib at the indicated times (arrows).
  • FIG. 7A shows the tumor volume of tumors in RPMI models after treatment with the indicated dose of carfilzomib at the indicated times (arrows).
  • FIG. 7B shows the body weight of the RPMI models after treatment with the indicated dose of carfilzomib at the indicated times (arrows).
  • FIG. 8A shows the tumor volume of tumors in H929 models after treatment with the indicated dose of hu38SB19 at the indicated times (top arrows) and the indicated dose of carfilzomib at the indicated times (bottom arrows).
  • FIG. 8B shows the body weight of the H929 models after treatment with the indicated dose of hu38SB19 at the indicated times (top arrows) and the indicated dose of carfilzomib at the indicated times (bottom arrows).
  • FIG. 9A is a graph showing the mean wet tumor weights of the H929 models after the indicated treatment with carfilzomib and/or hu38SB19 (mAb).
  • FIG. 9B is a graph showing the median wet tumor weights of the H929 models after the indicated treatment with carfilzomib and/or hu38SB19 (mAb).
  • FIG. 10A shows the tumor volume of tumors in RPMI-8226 models after treatment with the indicated dose of hu38SB19 at the indicated times (top arrows) and the indicated dose of carfilzomib at the indicated times (bottom arrows).
  • FIG. 10B shows the body weight of the RPMI-8226 models after treatment with the indicated dose of hu38SB19 at the indicated times (top arrows) and the indicated dose of carfilzomib at the indicated times (bottom arrows).
  • FIG. 11 is a graph showing the cell surface density of CD38 in multiple myeloma cell lines.
  • FIG. 12 is a graph showing that hu38SB19, as the sole active ingredient, results in dose-dependent anti-tumor effects and eradication of NCI-H929 hind-flank xenograft tumor growth.
  • FIG. 13 is a graph showing that low-dose combinations of carfilzomib and hu38SB19 results in near complete tumor growth inhibition of NCI-H929 xenografts.
  • the present invention relates to a method of treating a cancer in a subject which comprises administering one or more anti-CD38 antibodies and one or more carfilzomib compounds to the subject.
  • the cancer is a hematological malignancy.
  • the cancer is multiple myeloma.
  • the cancer is a relapsed multiple myeloma or a refractory multiple myeloma.
  • the one or more carfilzomib compounds is carfilzomib.
  • the one or more anti-CD38 antibodies are administered in an effective amount, preferably a synergistic amount.
  • the one or more anti-CD38 antibodies and/or the one or more carfilzomib compounds are administered in a therapeutically effective amount.
  • at least one of the one or more anti-CD38 antibodies is capable of killing a CD38+ cell by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC).
  • the antibody is hu38SB19.
  • At least one of the one or more anti-CD38 antibodies comprises one or more complementarity-determining region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 14, 81, 15, 16, 17, 18, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 and 36.
  • At least one of the one or more anti-CD38 antibodies is selected from the group consisting of: a) an antibody comprising a heavy chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOs: 13, 15 and either SEQ ID NO: 14 or SEQ ID NO: 81, and a light chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOs: 16, 17 and 18; b) an antibody comprising a heavy chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOs: 25, 26 and 27, and a light chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOs: 28, 29 and 30; c) an antibody comprising a heavy chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOs: 1, 2 and 3, and a light chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOs: 4, 5 and 6; d) an antibody comprising a heavy chain comprising a heavy
  • the antibody comprises a heavy chain having a VH variable region represented by SEQ ID NO: 66, and a light chain having a VL variable region represented by either SEQ ID NO: 62 or SEQ ID NO: 64. In some embodiments, the antibody comprises a heavy chain having a VH variable region represented by SEQ ID NO: 72, and a light chain having a VL variable region represented by either SEQ ID NO: 68 or SEQ ID NO: 70.
  • the one or more anti-CD38 antibodies are administered intravenously.
  • the one or more carfilzomib compounds are administered orally.
  • the one or more anti-CD38 antibodies and the one or more carfilzomib compounds are administered sequentially.
  • the method further comprises administering a dexamethasone compound, preferably dexamethasone, to the subject.
  • the dexamethasone compound is administered orally.
  • the dexamethasone compound is administered at a low dose.
  • the one or more anti-CD38 antibodies, the one or more carfilzomib compounds, and the dexamethasone compound are administered sequentially.
  • the one or more anti-CD38 antibodies and the one or more carfilzomib compounds are administered sequentially.
  • the present invention relates to a composition
  • a composition comprising a) at least one anti-CD38 antibody, preferably the antibody is capable of killing a CD38+ cell by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC); and b) at least one carfilzomib compound, preferably carfilzomib; and, optionally c) a dexamethasone compound, preferably dexamethasone.
  • the present invention relates to a composition comprising a) at least one anti-CD38 antibody; and b) at least one carfilzomib compound; and, optionally i) a dexamethasone compound.
  • the antibody is capable of killing a CD38+ cell by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC).
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement-dependent cytotoxicity
  • the antibody is hu38SB19.
  • the carfilzomib compound is carfilzomib.
  • the dexamethasone compound is dexamethasone.
  • the present invention is directed to a kit comprising a) a first composition comprising at least one anti-CD38 antibody, preferably the antibody is capable of killing a CD38+ cell by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC); and b) a second composition comprising at least one carfilzomib compound, preferably carfilzomib.
  • the compositions in the kit are packaged for sequential administration to a subject.
  • the antibody is hu38SB19.
  • the kit further includes a dexamethasone compound, preferably dexamethasone.
  • the carfilzomib compound and the dexamethasone compound are packaged for sequential administration to a subject.
  • the present invention is directed to a kit comprising at least one anti-CD38 antibody capable of killing a CD38+ cell by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC), packaged together with a label having one or more messages that the at least one anti-CD38 antibody shall be administered in combination with carfilzomib, and optionally with dexamethasone.
  • the antibody is hu38SB19.
  • the kit further includes a dexamethasone compound, preferably dexamethasone.
  • the carfilzomib compound and the dexamethasone compound are packaged for sequential administration to a subject.
  • the present invention is directed to a combination of: (i) at least one anti-CD38 antibody, preferably the antibody is capable of killing a CD38+ cell by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC); and (ii) at least one carfilzomib compound, preferably carfilzomib; and, optionally (iii) a dexamethasone compound, preferably dexamethasone.
  • the present invention relates to a combination comprising a) at least one anti-CD38 antibody; and b) at least one carfilzomib compound; and, optionally i) a dexamethasone compound.
  • the antibody is capable of killing a CD38+ cell by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC).
  • the antibody is hu38SB19.
  • the carfilzomib compound is carfilzomib.
  • the dexamethasone compound is dexamethasone.
  • the combination is for sequential use in the treatment of a hematological malignancy, preferably multiple myeloma.
  • the present invention is directed to use of (i) at least one anti-CD38 antibody, preferably the antibody is capable of killing a CD38+ cell by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC); and (ii) at least one carfilzomib compound, preferably carfilzomib; and, optionally (iii) a dexamethasone compound, preferably dexamethasone, for the treatment of a hematological malignancy, preferably multiple myeloma.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement-dependent cytotoxicity
  • the present invention relates to use of a) at least one anti-CD38 antibody; and b) at least one carfilzomib compound; and, optionally i) a dexamethasone compound, for the treatment of a hematological malignancy, preferably multiple myeloma.
  • the antibody is capable of killing a CD38+ cell by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC).
  • the antibody is hu38SB19.
  • the carfilzomib compound is carfilzomib.
  • the dexamethasone compound is dexamethasone.
  • the subject to be treated is mammalian. In some of the various embodiments of the present invention, the subject to be treated is a test animal such as a mouse. In some of the various embodiments of the present invention, the subject to be treated is human.
  • the present invention relates to methods of treating a cancer in a subject which comprises administering one or more anti-CD38 antibodies and one or more carfilzomib compounds to the subject.
  • “treat” or “treating” means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
  • the efficacy of a carfilzomib compound is considerably improved when administered in conjunction with one or more anti-CD38 antibodies according to the present invention.
  • anti-CD38 antibodies which exhibit (a) the capability of killing a CD38 + cell by apoptosis, (b) antibody-dependent cell-mediated cytotoxicity (ADCC), and (c) complement-dependent cytotoxicity (CDC) is believed to considerably improve the efficacy of carfilzomib compounds in the treatment of hematological malignancies, including MM, to a degree that is unexpectedly more than other anti-CD38 antibodies which do not exhibit all three (a)-(c) activities.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement-dependent cytotoxicity
  • the one or more anti-CD38 antibodies are capable of (a) killing a CD38 + cell by apoptosis, (b) antibody-dependent cell-mediated cytotoxicity (ADCC), and (c) complement-dependent cytotoxicity (CDC).
  • the one or more anti-CD38 antibodies and/or the one or more carfilzomib compounds are administered in a therapeutically effective amount.
  • a “therapeutically effective amount” of a substance refers to an amount of that substance that results in the alleviation of one or more symptoms, elimination of the causation of the symptoms either on a temporary or permanent basis, and/or the prevention or reduction in the appearance of symptoms of the named disorder or condition in the majority of subjects afflicted with and similarly treated for the named disease or disorder.
  • the cancer is one in which CD38 is expressed by the malignant cells.
  • the cancer is a hematological malignancy of the blood, bone marrow, and/or lymph nodes.
  • the cancer is a blood cancer.
  • Blood cancers include myeloma, lymphoma and leukemia.
  • the blood cancer might, for instance, be selected from the group consisting of multiple myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, hairy cell leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, and acute lymphocytic leukemia.
  • the cancer is multiple myeloma (MM).
  • the cancer is a relapse MM or refractory MM.
  • relapsed MM refers to clinically active MM after a period of remission and refractory MM refers to progressive or stable disease while being treated or progressive disease within 3 months of the last does of the prior treatment. See Dimopoulos et al. (2010) Eur J Haematology 88:1-15.
  • the subject is mammalian, preferably human. In some embodiments, the subject is an adult human, e.g., at least 18 years. In some embodiments, the subject is in need of treatment for the cancer. In some embodiments, the subject has been diagnosed as having the cancer. In some embodiments, the cancer is in partial or complete remission, however, the one or more carfilzomib compounds and the one or more anti-CD38 antibodies are administered to the subject so as to reduce the likelihood of relapse. In some embodiments, the subject has a Karnofsky performance status equal or superior to 60%.
  • the subject has undergone at least one or two prior therapies for multiple myeloma, induction therapy being considered one prior therapy.
  • the subject exhibits evidence that either the cancer progressed while the subject underwent a prior therapy, or that the subject was refractory to the prior therapy.
  • the anti-CD38 antibodies specifically bind CD38.
  • the anti-CD38 antibodies are raised against CD38 or an epitope thereof.
  • the anti-CD38 antibodies are monoclonal antibodies.
  • one or more of the anti-CD38 antibodies according to the present invention are monoclonal antibodies as described in WO 2008/047242, which is herein incorporated by reference in its entirety.
  • one or more of the anti-CD38 antibodies are monoclonal antibodies 38SB13, 38SB18, 38SB19, 38SB30, 38SB31, and 38SB39 as described in WO 2008/047242, which is herein incorporated by reference in its entirety.
  • the one or more anti-CD38 antibodies are capable of killing CD38 + cells by three different cytotoxic mechanisms, induction of apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC).
  • antibody is used herein in the broadest sense and includes monoclonal antibodies (including full length monoclonal antibodies) of any isotype such as IgG, IgM, IgA, IgD and IgE, polyclonal antibodies, multispecific antibodies, chimeric antibodies, and antibody fragments.
  • IgG IgG
  • IgM IgM
  • IgA IgA
  • IgD IgD
  • IgE polyclonal antibodies
  • multispecific antibodies chimeric antibodies
  • antibody fragments as used herein, the prefix “anti-” when in conjunction with an antigen, indicates that the given antibody is reactive with the given antigen.
  • An antibody reactive with a specific antigen can be generated by synthetic and/or recombinant methods such as selection of libraries of recombinant antibodies in phage or similar vectors, or by immunizing an animal with the antigen or an antigen-encoding nucleic acid.
  • a typical IgG antibody is comprised of two identical heavy chains and two identical light chains that are joined by disulfide bonds. Each heavy and light chain contains a constant region and a variable region. Each variable region contains three segments called “complementarity-determining regions” (“CDRs”) or “hypervariable regions”, which are primarily responsible for binding an epitope of an antigen. They are usually referred to as CDR1, CDR2, and CDR3, numbered sequentially from the N-terminus. The more highly conserved portions of the variable regions outside of the CDRs are called the “framework regions”.
  • CDRs complementarity-determining regions
  • V H refers to the variable region of an immunoglobulin heavy chain of an antibody, including the heavy chain of an Fv, scFv, dsFv, Fab, Fab′ or F(ab′) 2 fragment.
  • V L refers to the variable region of the immunoglobulin light chain of an antibody, including the light chain of an Fv, scFv, dsFv, Fab, Fab′ or F(ab′) 2 fragment.
  • the antibodies according to the present invention may be, e.g., murine, chimeric, and/or humanized antibodies.
  • a “chimeric antibody” is an antibody in which the constant region, or a portion thereof, is altered, replaced, or exchanged, so that the variable region is linked to a constant region of a different species, or belonging to another antibody class or subclass.
  • Chimeric antibody also refers to an antibody in which the variable region, or a portion thereof, is altered, replaced, or exchanged, so that the constant region is linked to a variable region of a different species, or belonging to another antibody class or subclass. Methods for producing chimeric antibodies are known in the art.
  • humanized antibody refers to a chimeric antibody which contain minimal sequence derived from non-human immunoglobulin.
  • Humanized antibodies, or antibodies adapted for non-rejection by other mammals may be produced using several technologies such as resurfacing and CDR grafting.
  • the resurfacing technology uses a combination of molecular modelling, statistical analysis and mutagenesis to alter the non-CDR surfaces of antibody variable regions to resemble the surfaces of known antibodies of the target host.
  • the CDR grafting technology involves substituting the complementarity determining regions of, for example, a mouse antibody, into a human framework domain, e.g., see WO 92/22653.
  • Humanized chimeric antibodies preferably have constant regions and variable regions other than the complementarity determining regions (CDRs) derived substantially or exclusively from the corresponding human antibody regions and CDRs derived substantially or exclusively from a mammal other than a human.
  • CDRs complementarity determining regions
  • Antibodies can be humanized using a variety of other techniques including CDR-grafting (EP 0 239 400; WO 91/09967; U.S. Pat. Nos. 5,530,101; and 5,585,089), veneering or resurfacing (EP 0 592 106; EP 0 519 596; Padlan E. A., 1991, Molecular Immunology 28(4/5): 489-498; Studnicka G. M. et al., 1994, Protein Engineering, 7(6): 805-814; Roguska M.
  • one or more of the anti-CD38 antibodies according to the invention are capable of killing a CD38 + cell by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). In some embodiments, one or more of the anti-CD38 antibodies according to the invention are capable of killing said CD38 + cells by apoptosis even in the absence of stroma cells or stroma-derived cytokines. These activities can be assessed as described in WO 2008/047242, which is hereby incorporated by reference in its entirety.
  • one or more anti-CD38 antibodies are selected from the group consisting of 38SB13, 38SB18, 38SB19, 38SB30, 38SB31, 38SB39, and antibodies cross-competing with 38SB13, 38SB18, 38SB19, 38SB30, 38SB31 or 38SB39.
  • the hybridoma cell lines producing the 38SB13, 38SB18, 38SB19, 38SB30, 38SB31, and 38SB39 murine anti-CD38 antibodies have been deposited at the American Type Culture Collection (10801 University Bld, Manassas, Va., 20110-2209, USA), on 21 Jun.
  • the anti-CD38 antibodies according to the present invention may, for instance, comprise a heavy chain comprising three sequential CDRs having amino acid sequences represented by SEQ ID NOs: 1, 2, and 3, and a light chain comprising three sequential CDRs having amino acid sequences represented by SEQ ID NOs: 4, 5, and 6.
  • An example of such an antibody is the 38SB13 antibody, which comprises a heavy chain having a V H variable region represented by SEQ ID NO: 50, and a light chain having a V L variable region represented by SEQ ID NO: 38.
  • the anti-CD38 antibodies according to the present invention may, for instance, comprise a heavy chain comprising three sequential CDRs having amino acid sequences represented by SEQ ID NOs: 7, 8, and 9, and a light chain comprising three sequential CDRs having amino acid sequences represented by SEQ ID NOs: 10, 11, and 12.
  • An example of such an antibody is the 38SB18 antibody, which comprises a heavy chain having a V H variable region represented by SEQ ID NO: 52 and a light chain having a V L variable region represented by SEQ ID NO: 40.
  • the anti-CD38 antibodies according to the present invention may, for instance, comprise a heavy chain comprising three sequential CDRs having amino acid sequences represented by SEQ ID NO: 13, SEQ ID NO: 15 and either SEQ ID NO: 14 or SEQ ID NO: 81, and a light chain comprising three sequential CDRs having amino acid sequences represented by SEQ ID NOs: 16, 17, and 18.
  • An example of such an antibody is the 38SB19 antibody, which comprises a heavy chain having a V H variable region represented by SEQ ID NO: 54 and a light chain having a V L variable region represented by SEQ ID NO: 42.
  • humanized versions of 38SB19 include antibodies comprising a heavy chain having a V H variable region represented by SEQ ID NO: 66, and a light chain having a V L variable region represented by either SEQ ID NO: 62 or SEQ ID NO: 64.
  • hu38SB19 is a humanized anti-CD38 antibody currently undergoing clinical evaluation in CD38-positive hematologic malignancies, including multiple myeloma. Previous and current studies demonstrate that the anti-myeloma activity associated with this agent involve mechanisms of ADCC, and CDC, as well as novel, direct apoptotic and anti-ADP-ribosyl cyclase activity.
  • the anti-CD38 antibodies according to the present invention may, for instance, comprise a heavy chain comprising three sequential CDRs having amino acid sequences represented by SEQ ID NOs: 19, 20, and 21, and a light chain comprising three sequential CDRs having amino acid sequences represented by SEQ ID NOs: 22, 23, and 24.
  • An example of such an antibody is the 38SB30 antibody, which comprises a heavy chain having a V H variable region represented by SEQ ID NO: 56 and a light chain having a V L variable region represented by SEQ ID NO: 44.
  • the anti-CD38 antibodies according to the present invention may, for instance, comprise a heavy chain comprising three sequential CDRs having amino acid sequences represented by SEQ ID NOs: 25, 26, and 27, and a light chain comprising three sequential CDRs having amino acid sequences represented by SEQ ID NOs: 28, 29, and 30.
  • An example of such an antibody is the 38SB31 antibody, which comprises a heavy chain having a V H variable region represented by SEQ ID NO: 58 and a light chain having a V L variable region represented by SEQ ID NO: 46.
  • humanized versions of 38SB31 include antibodies comprising a heavy chain having a V H variable region represented by SEQ ID NO: 72, and a light chain having a V L variable region represented by either SEQ ID NO: 68 or SEQ ID NO: 70.
  • the anti-CD38 antibodies according to the present invention may, for instance, comprise a heavy chain comprising three sequential CDRs having amino acid sequences represented by SEQ ID NOs: 31, 32 and 33, and a light chain comprising three sequential CDRs having amino acid sequences represented by SEQ ID NOs: 34, 35, and 36.
  • An example of such an antibody is the 38SB39 antibody, which comprises a heavy chain having a V H variable region represented by SEQ ID NO: 60 and a light chain having a V L variable region represented by SEQ ID NO: 48.
  • the anti-CD38 antibodies according to the invention are humanized antibodies consisting of two identical heavy chains and of two identical light chains, wherein each chain consists of one constant region and of one variable region.
  • a “carfilzomib compound” refers to carfilzomib (S)-4-Methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide and carfilzomib derivatives.
  • Carfilzomib derivatives refers to compounds which have 2-acetamido-N-(1-((1-(1-methylcyclopropyl)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)propanamide, i.e.,
  • carfilzomib derivatives include compounds which have the following structure, which may or may not be substituted, as part of its structural backbone:
  • X is selected from O, NH, and N—C 1-6 alkyl, preferably O.
  • Examples of “carfilzomib derivatives” according to the present invention include those as set forth in U.S. Pat. Nos. 7,232,818; 7,417,042; 7,491,704; 7,737,112; 8,129,346; 8,207,125; 8,207,126; 8,207,127; and 8,207,297.
  • the one or more anti-CD38 antibodies are administered in an effective amount.
  • an effective amount of the one or more anti-CD38 antibodies is an amount which results in an additive or a synergistic effect with the one or more carfilzomib compounds.
  • a “synergistic amount” is one that results in a synergistic effect.
  • a “synergistic effect” refers to the effect of the combination of the one or more anti-CD38 antibodies and the one or more carfilzomib compounds which is more than their expected additive effect.
  • the one or more anti-CD38 antibodies are administered before, during, and/or after the administration of the one or more carfilzomib compounds.
  • the one or more anti-CD38 antibodies and the one or more carfilzomib compounds are co-administered in the form of a single composition, e.g., as a mixture.
  • the present invention is directed to compositions comprising a mixture of at least one anti-CD38 antibody and at least one carfilzomib compound.
  • the mixture comprises the at least one anti-CD38 antibody in an amount that results in an additive or a synergistic effect with the at least one carfilzomib compound in a subject when both are administered.
  • the at least one anti-CD38 antibody in the mixture is one which is capable of killing a CD38 + cell by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC); and at least one carfilzomib compound.
  • the methods and compositions of the present invention are not exclusively limited to those which are obtained by physical association of the anti-CD38 antibodies and the carfilzomib compound, but also to those which permit a separate administration, which can be simultaneous or spaced out over a period of time.
  • the present invention is directed to a first composition comprising the one or more anti-CD38 antibodies, and a second composition comprising one or more carfilzomib compounds.
  • the at least one anti-CD38 antibody is one which is capable of killing a CD38 + cell by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC); and at least one carfilzomib compound.
  • the amount of the one or more anti-CD38 antibodies provided in the first composition is one that results in an additive or a synergistic effect with the at least one carfilzomib compound in the second composition in a subject when both are administered.
  • the first and second compositions may be packaged in a kit.
  • the present invention is directed to kits which comprise a first composition comprising the one or more anti-CD38 antibodies, and a second composition comprising one or more carfilzomib compounds.
  • the first and second composition may be mixed together before administering to a subject.
  • the first and second compositions may be administered either simultaneously or sequentially (i.e., spaced out over a period of time) so as to obtain the maximum efficacy, additivity, synergy, or a combination thereof of the combination.
  • kits comprising at least one anti-CD38 antibody packaged together with a label having one or more messages that the anti-CD38 antibody shall or might be administered in combination with carfilzomib and optionally with dexamethasone.
  • the kits according to the present invention may further comprise one or more messages that the antibody shall or might be administered to a subject suffering from a blood cancer such as multiple myeloma (e.g., relapsed or refractory multiple myeloma).
  • the one or more anti-CD38 antibodies in the kits of the present invention are those which are capable of killing a CD38 + cell by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC).
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement-dependent cytotoxicity
  • compositions of the present invention are pharmaceutical compositions.
  • pharmaceutical composition refers to a composition comprising at least one active principle (e.g., an anti-CD38 antibody or a carfilzomib compound) and at least one pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are well known to the skilled in the art, and usually depend on the chosen route of administration.
  • Pharmaceutical compositions according to the present invention may be provided in any form or formulation that is suitable for the chosen route of administration, such as e.g., a solution in case of an intravenous route of administration, e.g., capsules, pills or tablets in case of an oral route of administration, etc.
  • carfilzomib is typically administered intravenously.
  • carfilzomib might be administered intravenously, e.g., over 2 to 10 minutes, on two consecutive days each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28).
  • the recommended Cycle 1 dose is 20 mg/m 2 /day and, if tolerated, the doses of Cycle 2 and subsequent cycles are increased to 27 mg/m 2 /day.
  • patients are hydrated prior to and/or following administration. Since, however, co-administration of the one or more anti-CD38 antibodies and the one or more carfilzomib compounds results in an additive or a synergistic effect, the dosing of the carfilzomib compound may be adjusted accordingly, e.g., the dose changed and/or the dosing schedule modified. Of course, prescribing physicians might reconsider which dose and schedule to use depending on the condition and disease status of the patient and based upon clinical and laboratory findings.
  • the methods and compositions of the present invention may further include dexamethasone, which is member of the glucocorticoid class of steroid drugs, and acts as an anti-inflammatory and immunosuppressant.
  • the treatment methods of the present invention further comprise administering a dexamethasone compound to the subject being treated with the one or more anti-CD38 antibodies and the one or more carfilzomib compounds.
  • compositions and kits of the present invention which comprise the one or more anti-CD38 antibodies and/or the one or more carfilzomib compounds may further comprise a dexamethasone compound.
  • a “dexamethasone compound” refers to dexamethasone ((8S,9R,10S,11S,13S,14S,16R,17R)-9-Fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one) and dexamethasone derivatives.
  • a “dexamethasone derivative” refers to a compound having the following structural formula:
  • R1-R17 are each independently H, a halogen, an alkyl, an alkoxy, amino, or an alkylamine.
  • R1-R3 are H.
  • R4-R6 are methyl.
  • R7 is a halogen, preferably fluorine.
  • R8 is H.
  • R1-R3 are H, R4-R6 are methyl, R7 is a halogen, preferably fluorine, and R8 is H.
  • the dexamethasone compound may be administered orally. In some embodiments, the dexamethasone compound may be administered at the same or a lower dose than the dose recommended for dexamethasone by the EMA.
  • compositions of the present invention may be used as a medicament and/or for use in the manufacture of a medicament.
  • the compositions of the present invention may be used as a medicament and/or for use in the manufacture of a medicament for use in the treatment of a cancer such as a hematological malignancy of the blood, bone marrow, and/or lymph nodes, preferably a blood cancer.
  • hu38SB19 was provided in solution at 5 mg/ml, stored at 4° C. It was diluted into sterile saline in preparation for dosing, stored at 4° C. and used within 10 days of dilution.
  • Carfilzomib (PR-171) was obtained from Chemie Tek (CT-CARF 98). Carfilzomib was formulated in an aqueous solution of 10% (w/v) sulfobutylether-h-cyclodextrin (Cydex) and 10 mmol/L sodium citrate (pH 3.5), 2 mg/ml stock prepared and frozen at ⁇ 80° C., diluted daily with vehicle before injection. Carfilzomib was administered weekly qd ⁇ 2 ⁇ 3 wk (iv).
  • MM subcutaneous multiple myeloma
  • MM xenograft mouse models were established using NCI-H929 or RPMI-8226 cell lines. Specifically, 5-6 week old female Balb/c Scid mice were obtained from Jackson Lab. Mice were housed for 7-10 days prior to implantation. Mice were housed in a dedicated room in the UCSF Mt Zion Animal Barrier Facility.
  • NCI-H929 and RPMI-8226 cells were obtained from the German Collection of Microorganisms and Cell Cultures, DSMZ, (Deutsche Sammlung von Mikroorganismen and Zellkulturen), and grown in sterile suspension culture in T225 flasks as follows: NCI-H929: RPMI1640+20% FBS+4 mM L-glutamine+1 mM sodium pyruvate+50 ⁇ M mercaptoethanol. RPMI-8226: RPMI1640+10% FBS+4 mM L-glutamine.
  • mice were shaved on the right flank and shoulder region and anesthetized with ip avertin.
  • MM cells suspended in serum free RPMI 1640 media diluted 1:1 with Matrigel (BD) at a concentration of 1 ⁇ 10 8 cells per ml were injected sc into the right flank in 100 ⁇ L volume (1 ⁇ 10 7 cells) using a 1 ml syringe and 25 g needle.
  • Mice were monitored twice weekly for the appearance of tumors and once tumors were visible, measurements were collected twice weekly for body weight and tumor volume. Electronic balance and calipers were used and data was collected directly into a study management program (Study Director). When the mean tumor volume reached about 150-200 mm 3 , the mice were distributed into treatment groups of 8-10 mice per groups and dosing was begun.
  • the dosing schedule was hu38SB19 was 2 ⁇ /wk ⁇ 2 wk (iv, lateral tail vein) and carfilzomib was weekly qd ⁇ 2 ⁇ 3 wk (iv, lateral tail vein) (once per day, two days a week for three weeks).
  • Dose levels for use in combination studies are as follows:
  • the H929 model appears to be a more sensitive model to both agents while the RPMI model seems to be more resistant to the treatments even at the highest doses tested ( FIGS. 1A-7B ). Therefore in the combination studies, a suboptimal dose for each agent was chosen to evaluate the activity of the combination treatment (carfilzomib+hu38SB19) in the H929 model while higher doses of carfilzomib and hu38SB19 were tested in the RPMI model.
  • Antitumor activity was determined according to NCI standards based on the ratio of the median tumor volume change of the treated/median tumor volume change of the control ⁇ 100 (% ⁇ T/ ⁇ C). Low numerical values for ⁇ T/ ⁇ C describe stronger anti-tumor activity. Anti-tumor activity is defined as T/C ⁇ 40% at minimum. ⁇ T/ ⁇ C ⁇ 10% is considered high anti-tumor activity.
  • Carfilzomib is a second generation proteasome inhibitor which was recently approved to treat relapsed and refractory multiple myeloma patients. Inhibition of proteasome activity by carfilzomib results in a build-up of polyubiquinated proteins, which may cause cell cycle arrest, apoptosis, and inhibition of tumor growth.
  • Hu38SB19 has demonstrated multiple mechanisms of action including ADCC, CDC, and direct apoptosis induction.
  • hu38SB19 demonstrated potent direct pro-apoptotic activity on tumor cells without cross-linking. Thus, this unique property of hu38SB19 may also lead to greater tumor cell killing when in combination with carfilzomib compared to other CD38 antibodies combined with carfilzomib.
  • a clinical study for evaluating the effects of a treatment with hu38SB19 combined with carfilzomib in patients with relapsed or refractory multiple myeloma may be performed as described below.
  • the goals of the study may include:
  • Patients with relapsed multiple myeloma who have received at least two prior treatments (including bortezomib and thalidomide and/or lenalidomide) and whose disease has a less than or equal to 25% response to the most recent therapy or has disease progression during or within 60 days of the most recent therapy are enrolled.
  • Patients excluded from the trial are those having total bilirubin levels ⁇ 2 ⁇ upper limit of normal (ULN); creatinine clearance rates ⁇ 30 mL/min; New York Heart Association Class III to IV congestive heart failure; symptomatic cardiac ischemia; myocardial infarction within the last 6 months; peripheral neuropathy Grade 3 or 4, or peripheral neuropathy Grade 2 with pain; active infections requiring treatment; and pleural effusion.
  • Carfilzomib is administered intravenously over 2 to 10 minutes on two consecutive days each week for three weeks, followed by a 12-day rest period (28-day treatment cycle), until disease progression, unacceptable toxicity, or for a maximum of 12 cycles. Patients receive 20 mg/m 2 at each dose in Cycle 1, and 27 mg/m 2 in subsequent cycles.
  • dexamethasone 4 mg by mouth or by intravenous infusion may be administered prior to all carfilzomib doses during the first cycle and prior to all carfilzomib doses during the first dose-escalation (27 mg/m 2 ) cycle.
  • Dexamethasone premedication (4 mg orally or intravenously) may be reinstated if these symptoms reappeared during subsequent cycles.
  • Doses of hu38SB19 may be administered on the same days the carfilzomib doses are administered and/or on different days.
  • hu38SB19 and carfilzomib may be administered at the same time as one composition or as two separate compositions.
  • the study duration for an individual patient includes a screening period for inclusion of up to 21 days, and at least 4 weeks of treatment in the absence of severe adverse reaction, dose limiting toxicity or disease progression plus up to 60 days post-treatment follow up.
  • the total duration of the study may be up to one year.
  • CD38 Density was determined using anti-CD38-PE Quantibrite (BD Biosciences; Cat.342371) per the manufacturer's recommended protocols.
  • hu38SB19 was provided by Sanofi Oncology in solution at 5 mg/ml and stored at 4° C. hu38SB19 was diluted into sterile saline in preparation for dosing and used within 10 days of dilution. hu38SB19 was administered twice weekly ⁇ 2 wk IV. Carfilzomib (PR-171) was obtained from Chemie Tek (CT-CARF 98).
  • Carfilzomib was formulated in an aqueous solution of 10% (w/v) sulfobutylether-h-cyclodextrin (Cydex) and 10 mmol/L sodium citrate (pH 3.5), 2 mg/ml stock prepared and frozen at ⁇ 80° C., diluted daily with vehicle before injection. Carfilzomib was administered weekly qd ⁇ 2 ⁇ 3 wk (iv).
  • mice 5-6 week old female Balb/c Scid mice were obtained from Jackson Lab. Mice were housed for 7-10 days prior to implantation of multiple myeloma (MM) cell lines. Mice were housed in a dedicated room in the UCSF Mt. Zion Animal Barrier Facility.
  • MM myeloma
  • mice were shaved on the right flank and shoulder. MM cells were suspended in serum free RPMI 1640 media diluted 1:1 with Matrigel (BD) at a concentration of 1 ⁇ 10 8 cells per ml were injected sc into the right flank in 100 ul volume (1 ⁇ 10 7 cells) using a 1 ml syringe and 25 g needle. Mice were monitored twice weekly for the appearance of tumors and once tumors were visible, measurements were collected twice weekly for body weight and tumor volume. Electronic balance and calipers were used and data was collected directly into a study management program (Study Director). When the mean tumor volume reached approximately 150-200 mm 3 , mice were distributed into treatment groups of 8-10 mice per group and dosing was initiated.
  • BD Matrigel
  • hu38SB19 is a humanized anti-CD38 antibody whose anti-myeloma effects incorporate mechanisms of ADCC, CDC, and direct apoptosis.
  • FIG. 11 shows the cell surface density of CD38 in multiple myeloma cell lines. See Kim D, Park C Y, Medeiros B C, Weissman I L. CD19-CD45 low/ ⁇ CD38 high/CD138+ plasma cells enrich for human tumorigenic myeloma cells. Leukemia. 2012 December, 26(12):2530-7. CD38-positive multiple myeloma plasma cells demonstrate variable CD38 cell surface densities. All cell lines, with the exception of XG-6, are reported as CD38-positive.
  • hu38SB19 demonstrates potent anti-tumor effects in multiple myeloma xenografts, a disease largely characterized by neoplastic plasma cells expressing CD38.
  • FIG. 12 shows that single-agent administration of hu38SB19 results in dose-dependent inhibition of tumor growth in an NCI-H929 hind-flank model. The magnitude and significance of tumor growth inhibition at the end of the study increased with increased doses of hu38SB19.
  • FIG. 13 shows that a combined regimen of hu38SB19 and carfilzomib results in significant tumor growth inhibition in an NCI-H929 xenograft model that is not robustly sensitive to single-agent therapy with carfilzomib.

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