Combination therapies for treating cancer

Abstract

Provided are methods of treating cancer that comprise administering a polypeptide (e.g. a fusion polypeptide) that comprises a SIRPα D1 domain variant and an Fc domain variant in combination with at least one chemotherapy agent and/or at least one therapeutic antibody. Also provided are related kits.

1 . A method of treating cancer in an individual, comprising administering to the individual an effective amount of: (a) a polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant, and (b) a Bcl-2 inhibitor;
 wherein the SIRPα D1 domain variant comprises the amino acid sequence of SEQ ID NO: 81 or SEQ ID NO: 85; 
 wherein the Fc domain variant is 
 (i) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat; 
 (ii) a human IgG2 Fc region comprising A330S, P331S, and N297A mutations, wherein numbering is according to the EU index of Kabat; 
 (iii) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, and delG236 mutations, wherein numbering is according to the EU index of Kabat; or 
 (iv) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, delG236, and N297A mutations, wherein numbering is according to the EU index of Kabat. 
 
     
     
         2 - 7 . (canceled) 
     
     
         8 . A method of treating cancer in an individual, comprising administering to the individual an effective amount of: (a) a polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant, and (b) a platinum-based chemotherapy agent;
 wherein the SIRPα D1 domain variant comprises the amino acid sequence of SEQ ID NO: 81 or SEQ ID NO: 85; 
 wherein the Fc domain variant is 
 (i) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat; 
 (ii) a human IgG2 Fc region comprising A330S, P331S, and N297A mutations, wherein numbering is according to the EU index of Kabat; 
 (iii) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, and delG236 mutations, wherein numbering is according to the EU index of Kabat; or 
 (iv) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, delG236, and N297A mutations, wherein numbering is according to the EU index of Kabat. 
 
     
     
         9 - 11 . (canceled) 
     
     
         12 . A method of treating cancer in an individual, comprising administering to the individual an effective amount of: (a) a polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant, (b) a PD-1 inhibitor, (c) an antimetabolite, and (d) a platinum-based chemotherapy agent;
 wherein the SIRPα D1 domain variant comprises the amino acid sequence of SEQ ID NO: 81 or SEQ ID NO: 85; 
 wherein the Fc domain variant is 
 (i) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat; 
 (ii) a human IgG2 Fc region comprising A330S, P331S, and N297A mutations, wherein numbering is according to the EU index of Kabat; 
 (iii) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, and delG236 mutations, wherein numbering is according to the EU index of Kabat; or 
 (iv) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, delG236, and N297A mutations, wherein numbering is according to the EU index of Kabat, 
 wherein the cancer is head and neck squamous cell carcinoma (HNSCC), and wherein the individual has not received prior treatment for HNSCC. 
 
     
     
         13 . The method of  claim 12 , wherein the HNSCC is advanced and/or metastatic HNSCC. 
     
     
         14 . The method of  claim 12  or  13 , wherein the PD-1 inhibitor is an anti-PD-1 antibody. 
     
     
         15 . The method of  claim 14 , wherein the anti-PD-1 antibody is pembrolizumab, nivolumab, pidilizumab, cemiplimab, or BMS-936559. 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 12 , wherein the antimetabolite is 5-fluorouracil, 6-mercaptopurine, capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxycarbamide, methotrexate, pemetrexed, phototrexate. 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 12 , wherein the platinum-based chemotherapy agent is carboplatin, cisplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin. 
     
     
         20 - 21 . (canceled) 
     
     
         22 . A method of treating cancer in an individual, comprising administering to the individual an effective amount of: (a) a polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant, (b) an anti-HER2 antibody, and (c) an anti-PD-L1 antibody;
 wherein the SIRPα D1 domain variant comprises the amino acid sequence of SEQ ID NO: 81 or SEQ ID NO: 85; 
 wherein the Fc domain variant is 
 (i) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat; 
 (ii) a human IgG2 Fc region comprising A330S, P331S, and N297A mutations, wherein numbering is according to the EU index of Kabat; 
 (iii) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, and delG236 mutations, wherein numbering is according to the EU index of Kabat; or 
 (iv) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, delG236, and N297A mutations, wherein numbering is according to the EU index of Kabat. 
 
     
     
         23 - 28 . (canceled) 
     
     
         29 . A method of treating cancer in an individual, comprising administering to the individual an effective amount of: (a) a polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant, (b) an anti-HER2 antibody, (c) an anti-VEGF2 antibody, and (d) paclitaxel;
 wherein the SIRPα D1 domain variant comprises the amino acid sequence of SEQ ID NO: 81 or SEQ ID NO: 85; 
 wherein the Fc domain variant is 
 (i) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat; 
 (ii) a human IgG2 Fc region comprising A330S, P331S, and N297A mutations, wherein numbering is according to the EU index of Kabat; 
 (iii) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, and delG236 mutations, wherein numbering is according to the EU index of Kabat; or 
 (iv) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, delG236, and N297A mutations, wherein numbering is according to the EU index of Kabat, wherein the cancer is gastric cancer or gastroesophageal junction (GEJ) cancer, and wherein the individual has received at least one prior therapy for the gastric or the GEJ cancer. 
 
     
     
         30 . The method of  claim 29 , wherein the individual has received prior therapy with an anti-HER2 antibody, with an anti-HER2 antibody and a fluoropyrimidine, or with an anti HER2 antibody and a platinum-based chemotherapy agent. 
     
     
         31 . The method of  claim 29 , wherein the anti-HER2 antibody is trastuzumab. 
     
     
         32 . The method of  claim 29 , wherein the anti-VEGF antibody is ramucirumab. 
     
     
         33 . The method of  claim 29 , wherein the gastric cancer or the GEJ cancer is HER2 +  gastric cancer or HER2 +  GEJ cancer. 
     
     
         34 . The method of  claim 12  wherein the polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant is administered at a dose of 10 mg/kg once a week or at a dose of 15 mg/kg once a week. 
     
     
         35 . (canceled) 
     
     
         36 . A method of treating cancer in an individual, comprising administering to the individual an effective amount of (a) a polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant, and (b) an anti-TROP2 antibody;
 wherein the SIRPα D1 domain variant comprises the amino acid sequence of SEQ ID NO: 81 or SEQ ID NO: 85; 
 wherein the Fc domain variant is 
 (i) a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat; 
 (ii) a human IgG2 Fc region comprising A330S, P331S, and N297A mutations, wherein numbering is according to the EU index of Kabat; 
 (iii) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, and delG236 mutations, wherein numbering is according to the EU index of Kabat; or 
 (iv) a human IgG4 Fc region comprising S228P, E233P, F234V, L235A, delG236, and N297A mutations, wherein numbering is according to the EU index of Kabat. 
 
     
     
         37 - 39 . (canceled) 
     
     
         40 . The method of  claim 12 , wherein the Fc domain variant is a human IgG1 Fc region comprising L234A, L235A, G237A, and N297A mutations, wherein numbering is according to the EU index of Kabat. 
     
     
         41 . The method of  claim 40 , wherein the Fc domain variant comprises the amino acid sequence of SEQ ID NO: 91. 
     
     
         42 . The method of  claim 12 , wherein the polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant comprises the amino acid sequence of SEQ ID NO: 135 or 136. 
     
     
         43 . (canceled) 
     
     
         44 . The method of  claim 12 , wherein the polypeptide comprising a SIRPα D1 domain variant and an Fc domain variant forms a homodimer. 
     
     
         45 . The method of  claim 12 , wherein the individual is a human. 
     
     
         46 - 75 . (canceled)