Therapeutic sirp-alpha antibodies

Abstract

Anti-SIRPα monoclonal antibodies (anti-SIRPα mAbs), including multispecific SIRPα antibodies, are provided with distinct functional profiles as are related compositions and methods of using anti-SIRPα mAbs as therapeutics for the prevention and treatment of solid and hematological cancers. Also provided are amino acid sequences of exemplary anti-SIRPα monoclonal antibodies.

What is claimed is: 
     
         1 . A bispecific antibody comprising:
 a first antigen-binding domain that specifically binds human SIRPα and comprises a light chain variable domain (VL) and a heavy chain variable domain (VH), and   a second antigen-binding domain which specifically binds to a second antigen;   wherein the VL comprises LCDR1, LCDR2, LCDR3 sequences selected from:   i. SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3;   ii. SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6;   iii. SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9;   iv. SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12;   v. SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15;   vi. SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18;   vii. SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21;   viii. SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24;   ix. SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27;   x. SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30;   xi. SEQ ID NO:10, SEQ ID NO:31, SEQ ID NO:12;   xii. SEQ ID NO:10, SEQ ID NO:31, SEQ ID NO:32; and   xiii. SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27; and   wherein the VH comprises HCDR1, HCDR2, HCDR3 sequences selected from:   i. SEQ ID NO:33, SEQ ID NO:34, and SEQ ID NO:35;   ii. SEQ ID NO:36, SEQ ID NO:37, and SEQ ID NO:38;   iii. SEQ ID NO:39, SEQ ID NO:40, and SEQ ID NO:41;   iv. SEQ ID NO:42, SEQ ID NO:43, and SEQ ID NO:44;   v. SEQ ID NO:45, SEQ ID NO:46, and SEQ ID NO:47;   vi. SEQ ID NO:48, SEQ ID NO:49, and SEQ ID NO:50;   vii. SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53;   viii. SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56;   ix. SEQ ID NO:57, SEQ ID NO:58, and SEQ ID NO:59;   x. SEQ ID NO:60, SEQ ID NO:61, and SEQ ID NO:62; and   xi. SEQ ID NO:57, SEQ ID NO:58, and SEQ ID NO:63.   
     
     
         2 . The bispecific antibody of  claim 1 , wherein the VH comprises the sequence of any one of SEQ ID NOs:81-97 and the VL comprises the sequence of any one of SEQ ID NOs:64-80. 
     
     
         3 . The bispecific antibody of  claim 1 , wherein the wherein the VL comprises the LCDR1, LCDR2, LCDR3 sequences of SEQ ID NOs: 25, 26, and 27, and the VH comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 57, 58, and 59. 
     
     
         4 . The bispecific antibody of  claim 1 , wherein the VL comprises the sequence of SEQ ID NO: 72 and the VH comprises the sequence of SEQ ID NO: 89. 
     
     
         5 . The bispecific antibody of  claim 1 , wherein the wherein the VL comprises the LCDR1, LCDR2, LCDR3 sequences of SEQ ID NOs: 10, 11, and 12, and the VH comprises the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NOs: 42, 43, and 44. 
     
     
         6 . The bispecific antibody of  claim 1 , wherein the VL comprises the sequence of SEQ ID NO: 67 and the VH comprises the sequence of SEQ ID NO: 84. 
     
     
         7 . The bispecific antibody of  claim 1 , wherein the second antigen is selected from CD47, CD19, CD20, CD22, CD24, CD25, CD30, CD33, CD40, CD44, HER2, CD52, CD56, CD70, CD96, CD97, CD99, CD123, CD279 (PD-1), CD117, C-Met, PTHR2, EGFR, RANKL, SLAMF7, PD-L1, CD38, CD19/CD3, HAVCR2 (TIM3), and GD2. 
     
     
         8 . The bispecific antibody of  claim 1 , wherein the antibody is chimeric or humanized. 
     
     
         9 . The bispecific antibody of  claim 1 , wherein the antibody comprises a constant region of the isotype IgG1, IgG1-N297Q, IgG2, IgG4, IgG4-S228P, IgG4-PE or variants thereof. 
     
     
         10 . The bispecific antibody of  claim 9 , wherein the constant region is modified to increase or decrease an antibody effector function selected from antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), C1q binding, and altered binding to Fc receptors. 
     
     
         11 . The bispecific antibody of  claim 1 , which exhibits anti-tumor activity. 
     
     
         12 . The bispecific antibody of  claim 1 , which increases phagocytosis of human tumor cells. 
     
     
         13 . A pharmaceutical composition comprising the bispecific antibody of  claim 1 , and a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         14 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject the bispecific antibody of  claim 1 , in an amount effective to treat cancer. 
     
     
         15 . The method of  claim 14 , wherein the bispecific antibody is administered in combination with a chemotherapeutic agent. 
     
     
         16 . The method of  claim 14 , wherein the bispecific antibody is administered in combination with an antibody that increases the immune response to cancer. 
     
     
         17 . The method of  claim 16 , wherein the antibody that increases the immune response to cancer inhibits an immune checkpoint or modulates one or more co-stimulatory molecules. 
     
     
         18 . The method of  claim 14 , wherein the bispecific antibody is administered in combination with an opsonizing antibody which targets an antigen on a tumor cell. 
     
     
         19 . The method of  claim 18 , wherein the opsonizing antibody is selected from rituximab (anti-CD20), trastuzumab (anti-HER2), alemtuzumab (anti-CD52), cetuximab (anti-EGFR), panitumumab (anti-EGFR), ofatumumab (anti-CD20), denosumab (anti-RANKL), pertuzumab (anti-HER2), elotuzumab (anti-SLAMF7), atezolizumab (anti-PD-L1), avelumab (anti-PD-L1), durvalumab (anti-PD-L1), necitumumab (anti-EGFR), daratumumab (anti-CD38), obinutuzumab (anti-CD20), blinatumomab (anti-CD19/CD3), and dinutuximab (anti-GD2). 
     
     
         20 . The method of  claim 14 , wherein the cancer is selected from leukemia, lymphoma, multiple myeloma, ovarian cancer, breast cancer, endometrial cancer, colon cancer, rectal cancer, bladder cancer, urothelial cancer, lung cancer, bronchial cancer, bone cancer, prostate cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, gall bladder cancer, bile duct cancer, esophageal cancer, renal cell carcinoma, thyroid cancer, head and neck cancer, testicular cancer, cancer of the endocrine gland, cancer of the adrenal gland, cancer of the pituitary gland, cancer of the skin, cancer of soft tissues, cancer of blood vessels, cancer of brain, cancer of nerves, cancer of eyes, cancer of meninges, cancer of oropharynx, cancer of hypopharynx, cancer of cervix, and cancer of uterus, glioblastoma, meduloblastoma, astrocytoma, glioma, meningioma, gastrinoma, neuroblastoma, melanoma, myelodysplastic syndrome, and a sarcoma. 
     
     
         21 . The method of  claim 14 , wherein the cancer is non-small cell lung cancer, adenocarcinoma of the lung, or squamous cell carcinoma of the lung. 
     
     
         22 . The method of  claim 14 , wherein the cancer is selected from systemic mastocytosis, acute lymphocytic (lymphoblastic) leukemia (ALL), T-cell ALL, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), myeloproliferative disorder/neoplasm, myelodysplastic syndrome, monocytic cell leukemia, and plasma cell leukemia. 
     
     
         23 . The method of  claim 14 , wherein the cancer is a lymphoma selected from histiocytic lymphoma, T-cell lymphoma and B-cell lymphoma. 
     
     
         24 . The method of  claim 14 , wherein the cancer is low-grade/follicular non-Hodgkin's lymphoma (NHL), follicular center cell lymphoma (FCC), mantle cell lymphoma (MCL), diffuse large cell lymphoma (DLCL), small lymphocytic (SL) NHL, intermediate grade/follicular NHL, intermediate grade diffuse NHL, high grade immunoblastic NHL, high grade lymphoblastic NHL, high grade small non-cleaved cell NHL, bulky disease NHL, and Waldenstrom's Macroglobulinemia. 
     
     
         25 . The method of  claim 14 , wherein the cancer is a sarcoma selected from osteosarcoma, Ewing's sarcoma, leiomyosarcoma, synovial sarcoma, alveolar soft part sarcoma, angiosarcoma, liposarcoma, fibrosarcoma, rhabdomyosarcoma, and chrondrosarcoma.