# US 9,040,050 B2 · Combination treatment of CD38-expressing tumors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 9,040,050 B2 - Document ID: US9040050B2 - Status: Granted - Kind: B2 - Application number: 12/442,808 - Filed: 2007-09-26 - Published: 2010-04-15 - Granted: 2015-05-26 - Earliest claimed: 2006-09-26 - Assignees: Genmab A/S - Applicants: Jan Van De Winkel; Paul Parren; Yvo Graus; Judith Oprins; Michel De Weers; Martine Van Vugt; Ole Baadsgaard; Steen Lisby - Inventors: Jan Van De Winkel; Paul Parren; Yvo Graus; Judith Oprins; Michel De Weers; Martine Van Vugt; Ole Baadsgaard; Steen Lisby - Web page: https://patentgrep.com/patent/US9040050B2 ## CPC - A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines} - A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00) - A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) - A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone - A61K 31/69: Boron compounds - A61K 39/39558: {against tumor tissues, cells, antigens} - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 19/02: for joint disorders, e.g. arthritis, arthrosis - A61P 35/00: Antineoplastic agents - C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere} - A61K 2039/505: {comprising antibodies} - C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) ## Abstract The invention relates to novel method for the treatment of cancer using a combination therapy comprising an antibody that binds CD38, a corticosteroid and a non-corticosteroid chemotherapeutic agent. ## Claims ### Claim 1 A method for inhibiting growth and/or proliferation of multiple myeloma cells in an individual in need thereof, comprising administering to the individual i) an antibody that binds to residues KRN (SEQ ID NO: 70), corresponding to amino acid residues 268-270 of human CD38 (SEQ ID NO: 31), and residues VQTL (SEQ ID NO: 71), corresponding to amino acid residues 235-238 of human CD38 (SEQ ID NO: 31), ii) at least one corticosteroid, and iii) at least one non-corticosteroid chemotherapeutic agent. ### Claim 2 (depends on 1) The method of claim 1, further comprising administering autologous peripheral stem cells or bone marrow to the patient. ### Claim 3 (depends on 1) The method of claim 1, wherein said at least one non-corticosteroid chemotherapeutic agent comprises a cytotoxic agent or an angiogenesis inhibitor. ### Claim 4 (depends on 1) The method of claim 1, wherein said at least one non-corticosteroid chemotherapeutic agent comprises an alkylating agent. ### Claim 5 (depends on 1) The method of claim 1, wherein said at least one non-corticosteroid chemotherapeutic agent comprises one or more agents selected from the group consisting of: melphalan, mechlorethamine, thioepa, chlorambucil, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, dacarbazine (DTIC), procarbazine, mitomycin C, cisplatin and other platinum derivatives. ### Claim 6 (depends on 1) The method of claim 1, wherein said at least one non-corticosteroid chemotherapeutic agent comprises a glutamic acid derivative. ### Claim 7 (depends on 1) The method of claim 1, wherein said at least one non-corticosteroid chemotherapeutic agent comprises a proteasome inhibitor. ### Claim 8 (depends on 1) The method of claim 1, wherein said at least one non-corticosteroid chemotherapeutic agent comprises a vinca alkaloid. ### Claim 9 (depends on 1) The method of claim 1 wherein said at least one non-corticosteroid chemotherapeutic agent comprises an anthracycline. ### Claim 10 (depends on 1) The method of claim 1, wherein said at least one corticosteroid comprises a glucocorticoid. ### Claim 11 (depends on 1) The method of claim 1, wherein said at least one corticosteroid comprises prednisone. ### Claim 12 (depends on 1) The method of claim 1, wherein said at least one corticosteroid comprises prednisone and said at least one non-corticosteroid chemotherapeutic agent comprises melphalan. ### Claim 13 (depends on 1) The method of claim 1, wherein said at least one corticosteroid comprises prednisone and said at least one non-corticosteroid chemotherapeutic agent comprises thalidomide. ### Claim 14 (depends on 1) The method of claim 1, wherein said at least one corticosteroid comprises prednisone and said at least one non-corticosteroid chemotherapeutic agent comprises melphalan and thalidomide. ### Claim 15 (depends on 1) The method of claim 1, wherein said at least one corticosteroid comprises dexamethasone. ### Claim 16 (depends on 1) The method of claim 1, wherein said at least one corticosteroid comprises dexamethasone and said at least one non-corticosteroid chemotherapeutic agent comprises thalidomide or lenalidomide. ### Claim 17 (depends on 1) The method of claim 1, wherein said at least one corticosteroid comprises dexamethasone and said at least one non-corticosteroid chemotherapeutic agent comprises vincristine or doxorubicin. ### Claim 18 (depends on 1) The method of claim 1, comprising the further administration of interferon-alpha. ### Claim 19 (depends on 1) The method of claim 1, wherein said antibody is a monoclonal antibody. ### Claim 20 (depends on 1) The method of claim 1, wherein said antibody is a human monoclonal antibody. ### Claim 21 (depends on 1) The method of claim 1, wherein said antibody does not induce release of significant IL-6 by human monocytes or peripheral blood mononuclear cells. ### Claim 22 (depends on 1) The method of claim 1, wherein said antibody does not induce release of detectable IFN-γ by human T cells or peripheral blood mononuclear cells. ### Claim 23 (depends on 1) The method of claim 1, wherein said antibody is internalized by CD38 expressing cells. ### Claim 24 (depends on 1) The method of claim 1, wherein said antibody induces ADCC of CD38 expressing cells. ### Claim 25 (depends on 1) The method of claim 1, wherein said antibody induces CDC of CD38 expressing cells in the presence of complement. ### Claim 26 (depends on 1) The method of claim 1, wherein said antibody inhibits the synthesis of cGDPR. ### Claim 27 (depends on 1) The method of claim 1, wherein said antibody inhibits the synthesis of cADPR. ### Claim 28 (depends on 1) The method of claim 1, wherein said antibody comprises heavy and light chain CDR sequences set forth in SEQ ID NOs: 13-15 and 18-20, respectively. ### Claim 29 (depends on 28) The method of claim 28, wherein said antibody comprises heavy and light chain variable regions having the amino acid sequences set forth in SEQ ID No:12 and 17, respectively. ### Claim 30 (depends on 1) The method of claim 1, wherein said antibody is a full length IgG1, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM antibody. ### Claim 31 (depends on 1) The method of claim 1, wherein said antibody is an antibody fragment or a single-chain antibody. ### Claim 32 (depends on 1) The method of claim 1, wherein said antibody is conjugated to a cytotoxic agent, a radioisotope, or a drug. ### Claim 33 (depends on 1) The method of claim 1, wherein said antibody is a bispecific or multispecific molecule comprising a binding specificity for a human effector cell. ### Claim 34 (depends on 1) The method of claim 1, wherein said antibody is a bispecific or multispecific molecule comprising a binding specificity for CD3, CD4, CD138, IL-15R, membrane bound or receptor bound TNF-γ, a human Fc receptor, or membrane bound or receptor bound IL-15. ### Claim 35 (depends on 1) The method of claim 1, wherein said tumor cells are recurrent or refractory tumor cells. ### Claim 36 (depends on 1) The method of claim 1, wherein said individual has not responded to a previous anti-cancer treatment for the same cancer. ### Claim 37 (depends on 1) The method of claim 1, wherein said individual is enrolled to undergo subsequent autologous peripheral stem cell or bone marrow transplantation. ### Claim 38 (depends on 1) The method of claim 1, wherein the antibody, at least one corticosteroid and at least one non-corticosteroid chemotherapeutic agent are administered simultaneously. ### Claim 39 (depends on 1) The method of claim 1, wherein the antibody, at least one corticosteroid and at least one non-corticosteroid chemotherapeutic agent are administered sequentially. ### Claim 40 (depends on 1) The method of claim 1, wherein the antibody, at least one corticosteroid and at least one non-corticosteroid chemotherapeutic agent are all administered separately. ### Claim 41 (depends on 1) The method of claim 1, wherein the antibody, at least one corticosteroid and at least one non-corticosteroid chemotherapeutic agent are co-administered in one or two pharmaceutical compositions. ### Claim 42 (depends on 39) The method of claim 39, wherein the antibody is administered at least 1 day, before administration of said at least one corticosteroid and said at least one non-corticosteroid chemotherapeutic agent. ### Claim 43 (depends on 1) The method of claim 1, wherein the antibody is administered in a dose of 1 mg/kg or more. ### Claim 44 (depends on 1) The method of claim 1, wherein the antibody is administered once weekly for 2 to 12 weeks. ### Claim 45 (depends on 1) The method of claim 1 comprising administering a combination of corticosteroids. ### Claim 46 (depends on 1) The method of claim 1 comprising administering a combination of non-corticosteroid chemotherapeutic agents. ### Claim 47 (depends on 1) The method of claim 1, wherein said at least one corticosteroid comprises dexamethasone and said at least one non-corticosteroid chemotherapeutic agent comprises lenalidomide and bortezomib. ### Claim 48 (depends on 1) The method of claim 1, wherein said at least one corticosteroid comprises prednisone and said at least one non-corticosteroid chemotherapeutic agent comprises melphalan and bortezomib. ### Claim 49 (depends on 1) The method of claim 1, wherein the at least one corticosteroid comprises dexamethasone and said at least one non-corticosteroid chemotherapeutic agent comprises bortezomib. ### Claim 50 (depends on 6) The method of claim 6, wherein said glutamic acid derivative is thalidomide or a thalidomide analog. ### Claim 51 (depends on 7) The method of claim 7, wherein said proteasome inhibitor is bortezomib. ### Claim 52 (depends on 8) The method of claim 8, wherein said vinca alkaloid is vincristine. ### Claim 53 (depends on 9) The method of claim 9 wherein said anthracycline is doxorubicin. ### Claim 54 (depends on 1) The method of claim 1, wherein said at least one corticosteroid comprises dexamethasone and said at least one non-corticosteroid chemotherapeutic agent comprises thalidomide and lenalidomide. ### Claim 55 (depends on 1) The method of claim 1, wherein said at least one corticosteroid comprises dexamethasone and said at least one non-corticosteroid chemotherapeutic agent comprises vincristine and doxorubicin. ### Claim 56 A method for inhibiting growth and/or proliferation of tumor cells expressing CD38 in an individual in need thereof, comprising administering to the individual i) an antibody that specifically binds CD38, wherein the antibody comprises heavy and light chain variable region CDRs set forth in SEQ ID NOs: 13, 14, and 15 and SEQ ID NOs: 18, 19, and 20, respectively, ii) at least one corticosteroid, and iii) at least one non-corticosteroid chemotherapeutic agent. ### Claim 57 (depends on 56) The method of claim 56, wherein said antibody comprises heavy and light chain variable regions having the amino acid sequences set forth in SEQ ID No:12 and 17, respectively. ### Claim 58 (depends on 56) The method of claim 56, wherein said at least one non-corticosteroid chemotherapeutic agent comprises an alkylating agent. ### Claim 59 (depends on 56) The method of claim 56, wherein said at least one non-corticosteroid chemotherapeutic agent comprises one or more agents selected from the group consisting of: melphalan, mechlorethamine, thioepa, chlorambucil, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, dacarbazine (DTIC), procarbazine, mitomycin C, cisplatin and other platinum derivatives. ### Claim 60 (depends on 56) The method of claim 56, wherein said at least one non-corticosteroid chemotherapeutic agent comprises a glutamic acid derivative. ### Claim 61 (depends on 56) The method of claim 56, wherein said at least one non-corticosteroid chemotherapeutic agent comprises a proteasome inhibitor. ### Claim 62 (depends on 56) The method of claim 56, wherein said at least one non-corticosteroid chemotherapeutic agent comprises a vinca alkaloid. ### Claim 63 (depends on 56) The method of claim 56 wherein said at least one non-corticosteroid chemotherapeutic agent comprises an anthracycline. ### Claim 64 (depends on 56) The method of claim 56, wherein said at least one corticosteroid comprises a glucocorticoid. ### Claim 65 (depends on 56) The method of claim 56, wherein said at least one corticosteroid comprises prednisone. ### Claim 66 (depends on 56) The method of claim 56, wherein said at least one corticosteroid comprises dexamethasone and said at least one non-corticosteroid chemotherapeutic agent comprises lenalidomide and bortezomib. ### Claim 67 (depends on 56) The method of claim 56, wherein said at least one corticosteroid comprises prednisone and said at least one non-corticosteroid chemotherapeutic agent comprises melphalan and bortezomib. ### Claim 68 (depends on 56) The method of claim 56, wherein the at least one corticosteroid comprises dexamethasone and said at least one non-corticosteroid chemotherapeutic agent comprises bortezomib.