Anti-cd3 antibodies and uses thereof

Abstract

The present invention relates to antibodies that specifically bind CD3. The present invention relates to antibodies that specifically bind PSMA. The present invention relates to antibodies that specifically bind CD3 and PSMA. The invention relates to antibodies that specifically bind IL1RAP. The present invention relates to antibodies that specifically bind CD33. The present invention relates to antibodies that specifically bind CD3 and IL1RAP. The present invention relates to antibodies that specifically bind CD3 and CD33. The present invention relates to antibodies that specifically bind TMEFF2. The present invention relates to antibodies that specifically bind CD3 and TMEFF2. The present invention relates to fragments of the antibodies, polynucleotides encoding the antibodies or fragments thereof, and methods of making and using the same.

1 - 46 . (canceled) 
     
     
         47 . A recombinant multispecific antibody comprising a first domain, wherein the first domain specifically binds CD3, comprising a heavy chain variable region (VH) and a light chain variable region (VL) of SEQ ID NOs:652 and 661, respectively,
 wherein the multispecific antibody is an IgG1 isotype and comprises substitutions comprising (i) L234A and L235A, (ii) T366S, L368A, and Y407V substitutions, and (iii) T366W, and   wherein residue numbering is according to the EU Index.   
     
     
         48 . The recombinant multispecific antibody of  claim 47  comprising a second domain, wherein the second domain specifically binds a second antigen. 
     
     
         49 . The recombinant multispecific antibody of  claim 48 , wherein the second antigen is a cell surface antigen that is expressed on a target cell other than an immune effector cell. 
     
     
         50 . The recombinant multispecific antibody of  claim 49 , wherein the cell surface antigen is a tumor associated antigen. 
     
     
         51 . The recombinant multispecific antibody of  claim 48  comprising a third domain, wherein the third domain specifically binds a third antigen. 
     
     
         52 . The recombinant multispecific antibody of  claim 51 , wherein the third domain is covalently bound to a constant region of the antibody. 
     
     
         53 . The recombinant multispecific antibody of  claim 52 , wherein the third domain is an scFv. 
     
     
         54 . The recombinant multispecific antibody of  claim 51 , wherein the third antigen is a cell surface antigen that is expressed on a target cell other than an immune effector cell. 
     
     
         55 . The recombinant multispecific antibody of  claim 54 , wherein the cell surface antigen is a tumor associated antigen. 
     
     
         56 . A pharmaceutical composition comprising the recombinant multispecific antibody of  claim 51  and a pharmaceutically acceptable carrier. 
     
     
         57 . A polynucleotide encoding the isolated multispecific antibody of  claim 51 . 
     
     
         58 . A vector comprising the polynucleotide of  claim 57 . 
     
     
         59 . A host cell comprising the vector of  claim 58 . 
     
     
         60 . A method of producing the antibody of  claim 51 , comprising culturing a host cell comprising a polynucleotide encoding the antibody in conditions that the antibody is expressed, and recovering the antibody produced by the host cell. 
     
     
         61 . A method of treating a cancer in a subject, comprising administering a therapeutically effective amount of the isolated antibody of  claim 51  to the subject in need thereof for a time sufficient to treat the cancer. 
     
     
         62 . The method of  claim 61 , wherein the cancer is a solid tumor or a hematological malignancy. 
     
     
         63 . The method of  claim 62 , wherein the solid tumor is a prostate cancer, a colorectal cancer, a gastric cancer, a clear cell renal carcinoma, a bladder cancer, a lung cancer, a squamous cell carcinoma, a glioma, a breast cancer, a kidney cancer, a neovascular disorder, a clear cell renal carcinoma (CCRCC), a pancreatic cancer, a renal cancer, a urothelial cancer, or an adenocarcinoma to the liver. 
     
     
         64 . The method of  claim 63 , wherein the prostate cancer is a refractory prostate cancer, a prostatic intraepithelial neoplasia, an androgen independent prostate cancer, or a malignant prostate cancer. 
     
     
         65 . The method of  claim 62 , wherein the hematological malignancy is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), chronic myeloid leukemia (CML), or blastic plasmacytoid dendritic cell neoplasm (DPDCN). 
     
     
         66 . The method of  claim 61 , wherein the antibody is administered in combination with a second therapeutic agent. 
     
     
         67 . An isolated recombinant anti-CD3 antibody, or antigen-binding fragment thereof, comprising:
 (a) a VH comprising SEQ ID NO: 651 and a VL comprising SEQ ID NO: 658;   (b) a VH comprising SEQ ID NO: 652 and a VL comprising SEQ ID NO: 659;   (c) a VH comprising SEQ ID NO: 687 and a VL comprising SEQ ID NO: 688;   (d) a VH comprising SEQ ID NO: 653 and a VL comprising SEQ ID NO: 660;   (e) a VH comprising SEQ ID NO: 654 and a VL comprising SEQ ID NO: 659;   (f) a VH comprising SEQ ID NO: 655 and a VL comprising SEQ ID NO: 659; or   (g) a VH comprising SEQ ID NO 656 and a VL comprising SEQ ID NO: 659.