Anti-cd74 antibodies, compositions comprising anti-cd74 antibodies and methods of using anti-cd74 antibodies

Abstract

Provided herein are antibodies that selectively bind to CD74 and its isoforms and homologs, and compositions comprising the antibodies. Also provided are methods of using the antibodies, such as therapeutic and diagnostic methods.

1 . A method of treating cancer that expresses CD74 in a subject in need thereof, comprising administering to the subject an effective amount of an antibody comprising:
 a. three heavy chain CDRs of a V H  region selected from the group consisting of SEQ ID NOS: 236, 238, and 240, and three light chain CDRs of a V L  region selected from the group consisting of SEQ ID NOS: 256, 265, 267, 269, and 271.   
     
     
         2 . The method of  claim 1 , wherein the antibody comprises:
 a. three heavy chain CDRs and three light chain CDRs of the VH region SEQ ID NO: 236, and three light chain CDRs of the VL region SEQ ID NO: 267;   b. three heavy chain CDRs and three light chain CDRs of the VH region SEQ ID NO: 238, and the VL region SEQ ID NO: 256;   c. three heavy chain CDRs and three light chain CDRs of the VH region SEQ ID NO: 238, and the VL region SEQ ID NO: 265;   d. three heavy chain CDRs and three light chain CDRs of the VH region SEQ ID NO: 238, and the VL region SEQ ID NO: 267;   e. three heavy chain CDRs and three light chain CDRs of the VH region SEQ ID NO: 238, and the VL region SEQ ID NO: 269;   f. three heavy chain CDRs and three light chain CDRs of the VH region SEQ ID NO: 238, and the VL region SEQ ID NO: 271; or   g. three heavy chain CDRs and three light chain CDRs of the VH region SEQ ID NO: 240, and the VL region SEQ ID NO: 267.   
     
     
         3 . The method of  claim 1 , wherein the antibody comprises:
 a. a V H  comprising: a CDR-H1 comprising at least one of SEQ ID NOs: 11 and 43: a CDR-H2 comprising at least one of SEQ ID NOs: 75 and 107; and a CDR-H3 comprising SEQ ID NO: 139, and a V L  region comprising a CDR-L1 comprising SEQ ID NO:174: a CDR-L2 comprising SEQ ID NO:194, and a CDR-L3 comprising SEQ ID NO:214;   b. a V H  comprising: a CDR-H1 comprising at least one of SEQ ID NOs: 12 and 44: a CDR-H2 comprising at least one of SEQ ID NOs: 76 and 108; and a CDR-H3 comprising SEQ ID NO: 140, and a V L  region comprising a CDR-L1 comprising SEQ ID NO:165: a CDR-L2 comprising SEQ ID NO:185, and a CDR-L3 comprising SEQ ID NO:205;   c. a V H  comprising: a CDR-H1 comprising at least one of SEQ ID NOs: 12 and 44: a CDR-H2 comprising at least one of SEQ ID NOs: 76 and 108; and a CDR-H3 comprising SEQ ID NO: 140, and a V L  region comprising a CDR-L1 comprising SEQ ID NO:172: a CDR-L2 comprising SEQ ID NO:192, and a CDR-L3 comprising SEQ ID NO:212;   d. a V H  comprising: a CDR-H1 comprising at least one of SEQ ID NOs: 12 and 44: a CDR-H2 comprising at least one of SEQ ID NOs: 76 and 108; and a CDR-H3 comprising SEQ ID NO: 140, and a V L  region comprising a CDR-L1 comprising SEQ ID NO:174: a CDR-L2 comprising SEQ ID NO:194, and a CDR-L3 comprising SEQ ID NO:214;   e. a V H  comprising: a CDR-H1 comprising at least one of SEQ ID NOs: 12 and 44: a CDR-H2 comprising at least one of SEQ ID NOs: 76 and 108; and a CDR-H3 comprising SEQ ID NO: 140, and a V L  region comprising a CDR-L1 comprising SEQ ID NO:175: a CDR-L2 comprising SEQ ID NO:195, and a CDR-L3 comprising SEQ ID NO:215;   f. a V H  comprising: a CDR-H1 comprising at least one of SEQ ID NOs: 13 and 45: a CDR-H2 comprising at least one of SEQ ID NOs: 77 and 109; and a CDR-H3 comprising SEQ ID NO: 141, and a V L  region comprising a CDR-L1 comprising SEQ ID NO:174: a CDR-L2 comprising SEQ ID NO:194, and a CDR-L3 comprising SEQ ID NO:214; or   g. a V H  comprising: a CDR-H1 comprising at least one of SEQ ID NOs: 12 and 44: a CDR-H2 comprising at least one of SEQ ID NOs: 76 and 108; and a CDR-H3 comprising SEQ ID NO: 140, and a V L  region comprising a CDR-L1 comprising SEQ ID NO: 180: a CDR-L2 comprising SEQ ID NO: 200, and a CDR-L3 comprising SEQ ID NO: 220.   
     
     
         4 . The method of  claim 1 , wherein the antibody comprises:
 a. the V H  region SEQ ID NO: 236, and the V L  Trion SEQ ID NO: 267;   b. the V H  region SEQ ID NO: 238, and the V L  region SEQ ID NO: 256;   c. the V H  region SEQ ID NO: 238, and the V L  region SEQ ID NO: 265;   d. the V H  region SEQ ID NO: 238, and the V L  region SEQ ID NO: 267;   e. the V H  region SEQ ID NO: 238, and the V L  region SEQ ID NO: 269;   f. the V H  region SEQ ID NO: 238, and the V L  region SEQ ID NO: 271; or   g. the V H  region SEQ ID NO: 240, and the V L  region SEQ ID NO: 267.   
     
     
         5 . The method of  claim 1 , wherein the antibody comprises:
 a. a V H  region comprising: a CDR-H1 comprising at least one of SEQ ID NOs: 12 and 44; a CDR-H2 comprising at least one of SEQ ID NOs: 76 and 108; and a CDR-H3 comprising SEQ ID NO: 140; and   b. a V L  region comprising a CDR-L1 comprising SEQ ID NO: 174; a CDR-L2 comprising SEQ ID NO: 194, and a CDR-L3 comprising SEQ ID NO:214.   
     
     
         6 . A method of diagnosing cancer in a subject in need thereof, comprising administering to the subject an effective amount of an antibody comprising:
 a V H  region selected from the group consisting of SEQ ID NOS: 236, 238, and 240, and a V L  region selected from the group consisting of SEQ ID NOS: 256, 265, 267, 269, and 271, wherein the administration detects the expression of CD74 in cells and tissue thereby diagnosing cancer in the subject.   
     
     
         7 . The method of  claim 6 , wherein the antibody comprises:
 a. three heavy chain CDRs of the VH region SEQ ID NO: 236, and three light chain CDRs of the VL region SEQ ID NO: 267;   b. three heavy chain CDRs of the VH region SEQ ID NO: 238, and three light chain CDRs of the VL region SEQ ID NO: 256;   c. three heavy chain CDRs of the VH region SEQ ID NO: 238, and three light chain CDRs of the VL region SEQ ID NO: 265;   d. three heavy chain CDRs of the VH region SEQ ID NO: 238, and three light chain CDRs of the VL region SEQ ID NO: 267;   e. three heavy chain CDRs of the VH region SEQ ID NO: 238, and three light chain CDRs of the VL region SEQ ID NO: 269;   f. three heavy chain CDRs of the VH region SEQ ID NO: 238, and three light chain CDRs of the VL region SEQ ID NO: 271; or   g. three heavy chain CDRs of the VH region SEQ ID NO: 240, and three light chain CDRs of the VL region SEQ ID NO: 267.   
     
     
         8 . The method of  claim 6 , wherein the antibody comprises:
 a. a V H  comprising: a CDR-H1 comprising at least one of SEQ ID NOs: 11 and 43: a CDR-H2 comprising at least one of SEQ ID NOs: 75 and 107; and a CDR-H3 comprising SEQ ID NO: 139, and a V L  region comprising a CDR-L1 comprising SEQ ID NO:174: a CDR-L2 comprising SEQ ID NO:194, and a CDR-L3 comprising SEQ ID NO:214;   b. a V H  comprising: a CDR-H1 comprising at least one of SEQ ID NOs: 12 and 44: a CDR-H2 comprising at least one of SEQ ID NOs: 76 and 108; and a CDR-H3 comprising SEQ ID NO: 140, and a V L  region comprising a CDR-L1 comprising SEQ ID NO:165: a CDR-L2 comprising SEQ ID NO:185, and a CDR-L3 comprising SEQ ID NO:205;   c. a V H  comprising: a CDR-H1 comprising at least one of SEQ ID NOs: 12 and 44: a CDR-H2 comprising at least one of SEQ ID NOs: 76 and 108; and a CDR-H3 comprising SEQ ID NO: 140, and a V L  region comprising a CDR-L1 comprising SEQ ID NO:172: a CDR-L2 comprising SEQ ID NO:192, and a CDR-L3 comprising SEQ ID NO:212;   d. a V H  comprising: a CDR-H1 comprising at least one of SEQ ID NOs: 12 and 44: a CDR-H2 comprising at least one of SEQ ID NOs: 76 and 108; and a CDR-H3 comprising SEQ ID NO: 140, and a V L  region comprising a CDR-L1 comprising SEQ ID NO:174: a CDR-L2 comprising SEQ ID NO:194, and a CDR-L3 comprising SEQ ID NO:214;   e. a V H  comprising: a CDR-H1 comprising at least one of SEQ ID NOs: 12 and 44: a CDR-H2 comprising at least one of SEQ ID NOs: 76 and 108; and a CDR-H3 comprising SEQ ID NO: 140, and a V L  region comprising a CDR-L1 comprising SEQ ID NO:175: a CDR-L2 comprising SEQ ID NO:195, and a CDR-L3 comprising SEQ ID NO:215;   f. a V H  comprising: a CDR-H1 comprising at least one of SEQ ID NOs: 13 and 45: a CDR-H2 comprising at least one of SEQ ID NOs: 77 and 109; and a CDR-H3 comprising SEQ ID NO: 141, and a V L  region comprising a CDR-L1 comprising SEQ ID NO:174: a CDR-L2 comprising SEQ ID NO:194, and a CDR-L3 comprising SEQ ID NO:214; or   g. a V H  comprising: a CDR-H1 comprising at least one of SEQ ID NOs: 12 and 44: a CDR-H2 comprising at least one of SEQ ID NOs: 76 and 108; and a CDR-H3 comprising SEQ ID NO: 140, and a V L  region comprising a CDR-L1 comprising SEQ ID NO: 180; a CDR-L2 comprising SEQ ID NO: 200, and a CDR-L3 comprising SEQ ID NO: 220.   
     
     
         9 . The method of  claim 6 , wherein the antibody comprises:
 a. the V H  region SEQ ID NO: 236, and the V L  region SEQ ID NO: 267;   b. the V H  region SEQ ID NO: 238, and the V L  region SEQ ID NO: 256;   c. the V H  region SEQ ID NO: 238, and the V L  region SEQ ID NO: 265;   d. the V H  region SEQ ID NO: 238, and the V L  region SEQ ID NO: 267;   e. the V H  region SEQ ID NO: 238, and the V L  region SEQ ID NO: 269;   f. the V H  region SEQ ID NO: 238, and the V L  region SEQ ID NO: 271; or   g. the V H  region is SEQ ID NO: 240, and the V L  region is SEQ ID NO: 267.   
     
     
         10 . The method of  claim 1 , wherein the antibody comprises:
 a. V H  comprising: a CDR-H1 comprising at least one of SEQ ID NOs: 12 and 44; a CDR-H2 comprising at least one of SEQ ID NOs: 76 and 108; and a CDR-H3 comprising SEQ ID NO: 140; and   b. a V L  region comprising a CDR-L1 comprising SEQ ID NO: 174; a CDR-L2 comprising SEQ ID NO: 194, and a CDR-L3 comprising SEQ ID NO:214.   
     
     
         11 .- 39 . (canceled) 
     
     
         40 . The method of  claim 1 , wherein the antibody further comprises at least one constant region domain. 
     
     
         41 . The antibody of  claim 1 , wherein the constant region comprises a sequence selected from SEQ ID NOs: 304-305. 
     
     
         42 . The method of  claim 1 , wherein the antibody is a monoclonal antibody. 
     
     
         43 . The method of  claim 1 , wherein the antibody is an IgA, an IgD, an IgE, an IgG, or an IgM. 
     
     
         44 . The method of  claim 1 , wherein the antibody is humanized or human. 
     
     
         45 . The method of  claim 1 , wherein the antibody is aglycosylated. 
     
     
         46 . The method of  claim 1 , wherein the antibody is an antibody fragment. 
     
     
         47 . The antibody of  claim 46 , wherein the antibody fragment is selected from an Fv fragment, a Fab fragment, a F(ab′) 2  fragment, a Fab′ fragment, an scFv (sFv) fragment, and an scFv-Fc fragment. 
     
     
         48 . The antibody of  claim 47 , wherein the antibody is an scFv fragment. 
     
     
         49 . The antibody of  claim 48 , wherein the scFv fragment comprises a sequence selected from SEQ ID NOs: 221-228. 
     
     
         50 . The antibody of  claim 47 , wherein the antibody is an scFv-Fc fragment. 
     
     
         51 . The antibody of  claim 50 , wherein the scFv-Fc fragment comprises SEQ ID NO: 229. 
     
     
         52 . The method of  claim 1 , wherein the antibody has a k a  of at least about 10 5  M −1 ×sec −1  at a temperature of 25° C. 
     
     
         53 . The method of  claim 1 , wherein the antibody has a k d  of 10 −3  sec −1  or less at a temperature of 25° C. 
     
     
         54 . The method of  claim 1 , wherein the antibody has a K D  of 10 −9  M or less at a temperature of 25° C. 
     
     
         55 . The method of  claim 1 , wherein the antibody is internalized after binding to CD74 on the surface of a cell. 
     
     
         56 . The method of  claim 1 , wherein the Tm2 of the antibody is at least 75° C., 75.5° C., 76° C., 76.5° C., 77° C., 77.5° C., 78° C., 78.5° C., or 79° C. 
     
     
         57 . The method of  claim 1 , wherein the Tm1 of the antibody is less than 61° C. or less than 60° C. 
     
     
         58 .- 65 . (canceled) 
     
     
         66 . A pharmaceutical composition comprising the antibody of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         67 .- 69 . (canceled) 
     
     
         70 . The method of  claim 1 , wherein the cancer is selected from multiple myeloma, pancreatic cancer.