Anti-cd27 and anti-pd-l1 antibodies and bispecific constructs

Abstract

Provided herein are anti-CD27 and anti-PD-L1 antibodies, and binding domains thereof, as well as bispecific constructs and anti-CD27 binding domain linked to an anti-PD-L1 binding domain. Also provided herein are methods of stimulating T cell activity, methods of inducing or enhancing an immune response, and methods of treating a disease or condition by administering the bispecific constructs, antibodies, or antigen binding fragments thereof, or compositions described herein to a patient in need thereof.

1 . (canceled) 
     
     
         2 . A method for treating a condition or disease in a subject, the method comprising administering to the subject a bispecific construct in an amount effective to treat the condition or disease, wherein the bispecific construct comprises an anti-CD27 antibody binding domain which binds to human CD27 linked to an anti-PD-L1 antibody binding domain which binds to human PD-L1, wherein:
 (a) the anti-CD27 antibody binding domain comprises heavy chain CDR1, CDR2 and CDR3 regions comprising the amino acid sequences set forth in SEQ ID NOs:7, 8, and 9, respectively, and light chain CDR1, CDR2 and CDR3 regions comprising the amino acid sequences set forth in SEQ ID NOs:10, 11, and 12, respectively; and   (ii) the anti-PD-L1 antibody binding domain comprises heavy chain CDR1, CDR2 and CDR3 regions comprising the amino acid sequences set forth in SEQ ID NOs:59, 60, and 61, respectively, and light chain CDR1, CDR2 and CDR3 regions comprising the amino acid sequences set forth in SEQ ID NOs:62, 63, and 64, respectively, and   wherein the anti-CD27 antibody binding domain and the anti-PD-L1 antibody binding domain are linked by a peptide or a synthetic linker.   
     
     
         3 . The method of  claim 2 , wherein the anti-CD27 antibody binding domain comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:27 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:28. 
     
     
         4 . The method of  claim 2 , wherein the anti-PD-L1 antibody binding domain comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:87 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:88. 
     
     
         5 . The method of  claim 2 , wherein (a) the anti-PD-L1 antibody binding domain further comprises a human IgG1 constant domain or (b) the anti-CD27 antibody binding domain further comprises a human IgG1 constant domain or (c) the anti-PD-L1 antibody binding domain comprises a heavy chain and the anti-CD27 antibody binding domain is linked to the C-terminus of the heavy chain of the anti-PD-L1 antibody binding domain or (d) the anti-CD27 antibody binding domain comprises a heavy chain and the anti-PD-L1 antibody binding domain is linked to the C-terminus of the heavy chain of the anti-CD27 antibody binding domain. 
     
     
         6 . The method of  claim 2 , wherein the anti-CD27 antibody binding domain is a scFv or (b) the anti-PD-L1 antibody binding domain is a scFv. 
     
     
         7 . The method of  claim 2 , wherein the construct is encoded by the nucleotide sequence set forth in SEQ ID NO: 186. 
     
     
         8 . A method for treating a condition or disease in a subject, the method comprising administering to the subject a bispecific construct in an amount effective to treat the condition or disease, wherein the bispecific construct comprises a full-length anti-PD-L1 antibody which binds to human PD-L1 linked to an anti-CD27 scFv which binds to human CD27, wherein:
 (a) the anti-CD27 scFv comprises heavy chain CDR1, CDR2 and CDR3 regions comprising the amino acid sequences set forth in SEQ ID NOs:7, 8, and 9, respectively, and light chain CDR1, CDR2 and CDR3 regions comprising the amino acid sequences set forth in SEQ ID NOs:10, 11, and 12, respectively; and   (b) the anti-PD-L1 antibody comprises heavy chain CDR1, CDR2 and CDR3 regions comprising the amino acid sequences set forth in SEQ ID NOs: 59, 60, and 61, respectively, and light chain CDR1, CDR2 and CDR3 regions comprising the amino acid sequences set forth in SEQ ID NOs:62, 63, and 64, respectively, and a human IgG1 constant domain, and   wherein the anti-PD-L1 antibody and the anti-CD27 scFv are linked by a peptide or a synthetic linker.   
     
     
         9 . The method of  claim 8 , wherein the anti-PD-L1 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:87 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:88. 
     
     
         10 . The method of  claim 8 , wherein the bispecific construct comprises:
 (a) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:179 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 180; or   (b) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:181 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 182.   
     
     
         11 . A method for treating a condition or disease in a subject, the method comprising administering to the subject a bispecific construct in an amount effective to treat the condition or disease, wherein the bispecific construct comprises a full-length anti-CD27 antibody which binds to human CD27 linked to an anti-PD-L1 scFv which binds to human PD-L1, wherein:
 (a) the anti-CD27 antibody comprises heavy chain CDR1, CDR2 and CDR3 regions comprising the amino acid sequences set forth in SEQ ID NOs:7, 8, and 9, respectively, and light chain CDR1, CDR2 and CDR3 regions comprising the amino acid sequences set forth in SEQ ID NOs:10, 11, and 12, respectively and a human IgG1 constant domain; and   (b) the anti-PD-L1 scFv comprises heavy chain CDR1, CDR2 and CDR3 regions comprising the amino acid sequences set forth in SEQ ID NOs: 59, 60, and 61, respectively, and light chain CDR1, CDR2 and CDR3 regions comprising the amino acid sequences set forth in SEQ ID NOs:62, 63, and 64, respectively, and   wherein the anti-CD27 antibody and the anti-PD-L1 scFv are linked by a peptide or a synthetic linker.   
     
     
         12 . The method of  claim 11 , wherein the anti-CD27 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:27 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:28. 
     
     
         13 . A method for treating a condition or disease in a subject, the method comprising administering to the subject a bispecific construct in an amount effective to treat the condition or disease, wherein the bispecific construct comprises a full-length anti-PD-L1 antibody which binds to human PD-L1 linked to an anti-CD27 scFv which binds to human CD27, wherein:
 (a) the anti-CD27 scFv comprises heavy chain CDR1, CDR2 and CDR3 regions comprising the amino acid sequences set forth in SEQ ID NOs:7, 8, and 9, respectively, and light chain CDR1, CDR2 and CDR3 regions comprising the amino acid sequences set forth in SEQ ID NOs:10, 11, and 12, respectively; and   (b) the anti-PD-L1 antibody comprises heavy chain CDR1, CDR2 and CDR3 regions comprising the amino acid sequences set forth in SEQ ID NOs: 59, 60, and 61, respectively, and light chain CDR1, CDR2 and CDR3 regions comprising the amino acid sequences set forth in SEQ ID NOs:62, 63, and 64, respectively; and   (c) the anti-PD-L1 antibody further comprises a human IgG1 constant domain; and   (d) the anti-PD-L1 antibody and the anti-CD27 scFv comprise a fusion protein.   
     
     
         14 . The method of  claim 2 , wherein the subject suffers from a condition or disease in which stimulation of an immune response is desired. 
     
     
         15 . The method of  claim 14 , wherein the condition or disease is cancer. 
     
     
         16 . The method of  claim 15 , wherein the cancer is selected from the group consisting of colorectal cancer, ovarian cancer, renal cell carcinoma, head and neck squamous cell carcinoma and glioblastoma.