Bispecific Anti-CD28 X Anti-CD22 Antibodies and Uses Thereof

Abstract

The present invention provides bispecific antigen-binding molecules comprising a first antigen-binding domain that specifically binds human CD28, and a second antigen-binding molecule that specifically binds human CD-22. In certain embodiments, the bispecific antigen-binding molecules of the present invention are capable of inhibiting the growth of tumors expressing CD-22, such as B-cell lymphomas. The antibodies and bispecific antigen-binding molecules of the invention are useful for the treatment of diseases and disorders in which an up-regulated or induced targeted immune response is desired and/or therapeutically beneficial.

1 - 25 . (canceled) 
     
     
         26 . An isolated nucleic acid molecule comprising a nucleotide sequence encoding a heavy chain variable region (HCVR) of a bispecific antigen binding molecule comprising an antigen-binding domain that binds human CD28,
 wherein the HCVR comprises a heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 28, a heavy chain complementarity determining region 2 (HCDR2) comprising SEQ ID NO: 30, and a heavy chain complementarity determining region 3 (HCDR3) comprising SEQ ID NO: 32.   
     
     
         27 . An expression vector comprising the nucleic acid molecule of  claim 26 . 
     
     
         28 . A host cell comprising the expression vector of  claim 27 . 
     
     
         29 .- 35 . (canceled) 
     
     
         36 . The isolated nucleic acid molecule of  claim 26 , wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 26 
     
     
         37 . The isolated nucleic acid molecule of  claim 26 , wherein the HCVR comprises an HCDR1 encoded by the nucleotide sequence of SEQ ID NO:27, an HCDR2 encoded by the nucleotide sequence of SEQ ID NO:29, and an HCDR3 encoded by the nucleotide sequence of SEQ ID NO: 31. 
     
     
         38 . The isolated nucleic acid molecule of  claim 26 , wherein the nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO: 25 or a substantially identical sequence having at least 95% homology thereto. 
     
     
         39 . The isolated nucleic acid molecule of  claim 26 , wherein the nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO: 25. 
     
     
         40 . An isolated nucleic acid molecule comprising a nucleotide sequence encoding a heavy chain variable region (HCVR) of a bispecific antigen binding molecule comprising an antigen-binding domain that binds human CD22,
 wherein the HCVR comprises a heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 4, a heavy chain complementarity determining region 2 (HCDR2) comprising SEQ ID NO: 6, and a heavy chain complementarity determining region 3 (HCDR3) comprising SEQ ID NO: 8.   
     
     
         41 . The isolated nucleic acid molecule of  claim 40 , wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 2. 
     
     
         42 . The isolated nucleic acid molecule of  claim 40 , wherein the HCVR comprises an HCDR1 encoded by the nucleotide sequence of SEQ ID NO:3, an HCDR2 encoded by the nucleotide sequence of SEQ ID NO:5, and an HCDR3 encoded by the nucleotide sequence of SEQ ID NO: 7. 
     
     
         43 . The isolated nucleic acid molecule of  claim 40 , wherein the nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO: 1 or a substantially identical sequence having at least 95% homology thereto. 
     
     
         44 . The isolated nucleic acid molecule of  claim 26 , wherein the nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO: 1. 
     
     
         45 . An expression vector comprising the nucleic acid molecule of  claim 40 . 
     
     
         46 . A host cell comprising the expression vector of  claim 45 . 
     
     
         47 . An isolated nucleic acid molecule comprising a nucleotide sequence encoding a light chain variable region (LCVR) of a bispecific antigen binding molecule comprising an antigen-binding domain that binds human CD28 and human CD22,
 wherein the LCVR comprises a light chain complementarity determining region 1 (LCDR1) comprising SEQ ID NO: 12, a light chain complementarity determining region 2 (LCDR2) comprising SEQ ID NO: 14, and a light chain complementarity determining region 3 (LCDR3) comprising SEQ ID NO: 16.   
     
     
         48 . The isolated nucleic acid molecule of  claim 47 , wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 10. 
     
     
         49 . The isolated nucleic acid molecule of  claim 47 , wherein the LCVR comprises an LCDR1 encoded by the nucleotide sequence of SEQ ID NO:11, an LCDR2 encoded by the nucleotide sequence of SEQ ID NO:13, and an LCDR3 encoded by the nucleotide sequence of SEQ ID NO: 15. 
     
     
         50 . The isolated nucleic acid molecule of  claim 47 , wherein the nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO: 9 or a substantially identical sequence having at least 95% homology thereto. 
     
     
         51 . The isolated nucleic acid molecule of  claim 47 , wherein the nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO: 9. 
     
     
         52 . An expression vector comprising the nucleic acid molecule of  claim 47 . 
     
     
         53 . A host cell comprising the expression vector of  claim 52 . 
     
     
         54 . A host cell comprising:
 (a) a nucleic acid molecule comprising a nucleic acid sequence encoding a heavy chain variable region (HCVR) of a bispecific antigen binding molecule comprising an antigen binding domain that binds human CD28, wherein the HCVR comprises a heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 28, a heavy chain complementarity determining region 2 (HCDR2) comprising SEQ ID NO: 30, and a heavy chain complementarity determining region 3 (HCDR3) comprising SEQ ID NO: 32;   (b) a nucleic acid molecule comprising a nucleic acid sequence encoding a heavy chain variable region (HCVR) of a bispecific antigen binding molecule comprising an antigen binding domain that binds human CD22, wherein the HCVR comprises a heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 4, a heavy chain complementarity determining region 2 (HCDR2) comprising SEQ ID NO: 6, and a heavy chain complementarity determining region 3 (HCDR3) comprising SEQ ID NO: 8; and   (c) a nucleic acid molecule comprising a nucleic acid sequence encoding a light chain variable region (LCVR) of a bispecific antigen binding molecule comprising an antigen binding domain that binds human CD28 and human CD22, wherein the LCVR comprises a light chain complementarity determining region 1 (LCDR1) comprising SEQ ID NO: 12, a light chain complementarity determining region 2 (LCDR2) comprising SEQ ID NO: 14, and a light chain complementarity determining region 3 (LCDR3) comprising SEQ ID NO: 16.   
     
     
         55 . A method of producing a bispecific antigen binding molecule that binds human CD28 and human CD22, the method comprising growing the host cell of  claim 54  under conditions permitting production of the bispecific antigen binding molecule, wherein said host cell comprises the nucleic acid molecule comprising the nucleic acid sequence encoding the HCVR of the antigen binding domain that binds human CD28, the nucleic acid molecule comprising the nucleic acid sequence encoding the HCVR of the antigen binding domain that binds human CD22, and the nucleic acid molecule comprising the nucleic acid sequence encoding the LCVR of the antigen binding domain that binds human CD28 and CD22. 
     
     
         56 . A composition comprising:
 a first nucleic acid molecule wherein the first nucleic acid molecule comprises a nucleic acid sequence encoding a heavy chain variable region (HCVR) of a bispecific antigen binding molecule comprising an antigen binding domain that binds human CD28 that comprises a heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 28, a heavy chain complementarity determining region 2 (HCDR2) comprising SEQ ID NO: 30, and a heavy chain complementarity determining region 3 (HCDR3) comprising SEQ ID NO: 32;   a second nucleic acid molecule wherein the second nucleic acid molecule comprises a nucleic acid sequence encoding a heavy chain variable region (HCVR) of a bispecific antigen binding molecule comprising an antigen binding domain that binds human CD22 that comprises a heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 4, a heavy chain complementarity determining region 2 (HCDR2) comprising SEQ ID NO: 6, and a heavy chain complementarity determining region 3 (HCDR3) comprising SEQ ID NO: 8; and   a third nucleic acid molecule wherein the third nucleic acid molecule comprises a nucleic acid sequence encoding a light chain variable region (LCVR) of a bispecific antigen binding molecule comprising an antigen binding domain that binds human CD28 and human CD22 that comprises a light chain complementarity determining region 1 (LCDR1) comprising SEQ ID NO: 12, a light chain complementarity determining region 2 (LCDR2) comprising SEQ ID NO: 14, and a light chain complementarity determining region 3 (LCDR3) comprising SEQ ID NO: 16.   
     
     
         57 . The composition of  claim 57 , wherein the HCVR of the bispecific antigen binding molecule comprising an antigen binding domain that binds human CD28 comprises SEQ ID NO: 26, wherein the HCVR of the bispecific antigen binding molecule comprising an antigen binding domain that binds human CD22 comprises SEQ ID NO: 2, and wherein the LCVR of the bispecific antigen binding molecule comprising an antigen binding domain that binds human CD28 and human CD22 comprises SEQ ID NO: 10.