# US 11,078,279 B2 · Combination therapy for the treatment of cancer > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,078,279 B2 - Document ID: US11078279B2 - Status: Granted - Kind: B2 - Application number: 15/580,969 - Filed: 2016-06-09 - Published: 2018-10-18 - Granted: 2021-08-03 - Earliest claimed: 2015-06-12 - Assignees: MacroGenics, Inc. - Applicants: MacroGenics, Inc. - Inventors: Jon Marc Wigginton; Naimish Bharat Pandya; Robert Joseph Lechleider; Scott Koenig; Ezio Bonvini - Web page: https://patentgrep.com/patent/US11078279B2 ## CPC - C07K 16/2818: {against CD28 or CD152} - A61P 35/00: Antineoplastic agents - C07K 16/2803: {against the immunoglobulin superfamily} - C07K 16/2863: {against receptors for growth factors, growth regulators} - C07K 16/32: against translation products of oncogenes - A61K 2039/505: {comprising antibodies} - C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered - C07K 2317/41: Glycosylation, sialylation, or fucosylation - C07K 2317/524: CH2 domain - C07K 2317/526: CH3 domain - C07K 2317/567: Framework region [FR] - C07K 2317/71: Decreased effector function due to an Fc-modification - C07K 2317/72: Increased effector function due to an Fc-modification - C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation - C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC] - C07K 2317/74: Inducing cell proliferation - C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding - C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value - 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) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - 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) ## Abstract This invention relates to a pharmaceutical composition that comprises a first molecule that specifically binds HER2/neu and a second molecule that specifically binds a cell-surface receptor (or its ligand) that is involved in regulating an immune checkpoint (or the ligand thereof). The invention particularly relates to the embodiment wherein the second molecule binds to PD-1. The invention also relates to the use of such pharmaceutical compositions to treat cancer and other diseases. ## Claims ### Claim 1 A method of treating cancer, comprising administering to a subject in need thereof: (A) a Variant Chimeric 4D5 Antibody comprising a light chain variable domain comprising the amino acid sequence of SEQ ID NO:4, and a heavy chain that comprises a variant Fc Region that exhibits enhanced ADCC activity relative to a comparable antibody that comprises a wild-type IgG1 Fc Region, wherein said heavy chain comprises an amino acid sequence selected from the group consisting of SEQ ID NO:9, SEQ ID NO:11, and SEQ ID NO:13, and (B) an anti-PD-1 antibody or a molecule that specifically binds PD-1 that comprises an antigen-binding fragment of said anti-PD-1 antibody, wherein said anti-PD-1 antibody and said antigen-binding fragment comprise: (a) a variant Fc Region that comprises at least one modification relative to a wild-type IgG1 Fc Region or an IgG4 Fc Region, wherein said variant Fc Region of said molecule exhibits reduced ADCC activity relative to a comparable molecule that comprises said wild-type IgG1 Fc Region; and (b) (1) the three heavy chain CDRs and the three light chain CDRs of antibody hPD-1 mAb 2; (2) the three heavy chain CDRs and the three light chain CDRs of antibody PD-1 mAb 6-ISQ; (3) the three heavy chain CDRs and the three light chain CDRs of antibody hPD-1 mAb 7; (4) the three heavy chain CDRs and the three light chain CDRs of antibody hPD-1 mAb 9; or (5) the three heavy chain CDRs and the three light chain CDRs of antibody hPD-1 mAb 15. ### Claim 2 (depends on 1) The method of claim 1 wherein said anti-PD-1 antibody and said molecule that comprises an antigen-binding fragment of said anti-PD-1 antibody comprise: (1) the heavy chain variable domain and the light chain variable domain of antibody hPD-1 mAb 2; (2) the heavy chain variable domain and the light chain variable domain of antibody PD-1 mAb 6-ISQ; (3) the heavy chain variable domain and the light chain variable domain of antibody hPD-1 mAb 7; (4) the heavy chain variable domain and the light chain variable domain of antibody hPD-1 mAb 9; (5) the heavy chain variable domain and the light chain variable domain of antibody hPD-1 mAb 15. ### Claim 3 (depends on 1) The method of claim 1, wherein said method comprises administering anti-PD-1 antibody hPD-1 mAb 2, antibody PD-1 mAb 6-ISQ, antibody hPD-1 mAb 7, antibody hPD-1 mAb 9, or antibody hPD-1 mAb 15 to said subject. ### Claim 4 (depends on 1) The method of claim 1, wherein said Variant Chimeric 4D5 Antibody is administered at a dosage of approximately 6-18 mg/kg every three weeks and said anti-PD-1 antibody is administered at a fixed dosage of approximately 50 mg to 500 mg, every three weeks. ### Claim 5 (depends on 1) The method of claim 1, wherein said Variant Chimeric 4D5 Antibody is administered at a dosage of approximately 6-18 mg/kg every three weeks and said anti-PD-1 antibody is administered at a dosage of approximately 1-10 mg/kg, every three weeks. ### Claim 6 (depends on 4) The method of claim 4, wherein said Variant Chimeric 4D5 Antibody is administered at a dosage selected from the group consisting of 6 mg/kg, 10 mg/kg, 15 mg/kg and 18 mg/kg, every three weeks. ### Claim 7 (depends on 5) The method of claim 5 wherein said anti-PD-1 antibody is administered at a dosage selected from the group consisting of 1 mg/kg, 2 mg/kg, 3 mg/kg and 10 mg/kg, every three weeks. ### Claim 8 (depends on 1) The method of claim 1, wherein said Variant Chimeric 4D5 Antibody and said anti-PD-1 antibody or said molecule that comprises an antigen-binding fragment of said anti-PD-1 antibody are administered concurrently to said subject in a single pharmaceutical composition. ### Claim 9 (depends on 1) The method of claim 1, wherein said Variant Chimeric 4D5 Antibody and said anti-PD-1 antibody or said molecule that comprises an antigen-binding fragment of said anti-PD-1 antibody are administered concurrently to said subject in separate pharmaceutical compositions, wherein said separate compositions are administered within a 24-hour period. ### Claim 10 (depends on 1) The method of claim 1, wherein said Variant Chimeric 4D5 Antibody and said anti-PD-1 antibody or said molecule that comprises an antigen-binding fragment of said anti-PD-1 antibody are administered sequentially to said subject in separate pharmaceutical compositions, wherein the second administered composition is administered at least 24 hours after the administration of the first administered composition. ### Claim 11 (depends on 1) The method of claim 1, wherein said cancer is a cancer in which HER2/neu is expressed. ### Claim 12 (depends on 11) The method of claim 11, wherein said cancer is a breast cancer, gastric cancer, prostate cancer, uterine cancer, ovarian cancer, colon cancer, endometrial cancer, adrenal carcinoma, non-small cell lung cancer, head and neck cancer, laryngeal cancer, liver cancer, renal cancer, glioblastoma, or pancreatic cancer. ### Claim 13 (depends on 1) The method of claim 1, wherein said treatment further comprises the step of administering a third therapeutic agent, wherein said third therapeutic agent is selected from the group consisting of an anti-angiogenic agent, an anti-neoplastic agent, a chemotherapeutic agent, and a cytotoxic agent. ### Claim 14 (depends on 13) The method of claim 13, wherein the third therapeutic agent is administered concurrently with said Variant Chimeric 4D5 Antibody and/or said anti-PD-1 antibody or said molecule that comprises an antigen-binding fragment of said anti-PD-1 antibody. ### Claim 15 (depends on 13) The method of claim 13, wherein the third therapeutic agent is administered separately from said Variant Chimeric 4D5 Antibody and/or said anti-PD-1 antibody or said molecule that comprises an antigen-binding fragment of said anti-PD-1 antibody. ### Claim 16 (depends on 1) The method of claim 1, wherein said Variant Chimeric 4D5 Antibody is margetuximab. ### Claim 17 (depends on 3) The method of claim 3 wherein said anti-PD-1 antibody is antibody hPD-1 mAb 7. ### Claim 18 (depends on 1) The method of claim 1, wherein: (a) said Variant Chimeric 4D5 Antibody is for administration at a dosage of approximately 6-18 mg/kg and said anti-PD-1 antibody is for administration at a fixed dosage of approximately 100-500 mg; or (b) said Variant Chimeric 4D5 Antibody is for administration at a dosage of approximately 6-18 mg/kg and said anti-PD-1 antibody is for administration at a dosage of approximately 1-10 mg/kg. ### Claim 19 (depends on 3) The method of claim 3, wherein said anti-PD-1 antibody is PD-1 mAb 6-ISQ. ### Claim 20 (depends on 3) The method of claim 3, wherein: (a) said Variant Chimeric 4D5 Antibody is for administration at a dosage of approximately 6-18 mg/kg and said anti-PD-1 antibody is for administration at a fixed dosage of approximately 100-500 mg; or (b) said Variant Chimeric 4D5 Antibody is for administration at a dosage of approximately 6-18 mg/kg and said anti-PD-1 antibody is for administration at a dosage of approximately 1-10 mg/kg.