Anti-sez6l2 antibodies and antibody drug conjugates

Abstract

Disclosed herein are anti-Seizure Related 6 Homolog Like 2 (SEZ6L2) antibodies and antibody drug conjugates (ADCs), including compositions and methods of using said antibodies and ADCs.

1 . An anti-human Seizure Related 6 Homolog Like 2 (anti-hSEZ6L2) antibody, or antigen binding portion thereof, that
 a) inhibits tumor growth in an in vivo human small-cell lung carcinoma (SCLC) xenograft assay with a tumor growth inhibition % (TGI %) of at least about 50% relative to a human IgG antibody which is not specific for SEZ6L2, wherein the human IgG antibody is administered in the SCLC xenograft assay at the same dose and frequency as the anti-hSEZ6L2 antibody, or antigen binding portion thereof; and   b) does not bind to SEZ6 or SEZ6L.   
     
     
         2 .- 5 . (canceled) 
     
     
         6 . The antibody, or antigen binding portion thereof, of  claim 1 , wherein the antibody, or antigen binding portion thereof, comprises:
 a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 3, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 8, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 7, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 6;   a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 19, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 18, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 24, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 23, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 22;   a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 28, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 27, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 31, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 15, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 30;   a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 43, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 42, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 41, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 46, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 45;   a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 50, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48;   a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 62, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 61, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:60, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 66, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 65, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 64;   a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 72, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 65, and a CDR 1 domain comprising the amino acid sequence of SEQ ID NO: 64;   a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 76, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 74, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 78, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48;   a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 81, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 75, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 80, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 83, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 49, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 48;   a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 87, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 86, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 85, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR 1 domain comprising the amino acid sequence of SEQ ID NO: 37;   a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 93, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 92, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 91, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 95, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR 1 domain comprising the amino acid sequence of SEQ ID NO: 37;   a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 99, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 98, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 97, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 103, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 102, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 101;   a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 107, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 106, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 105, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 89, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37;   a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 112, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 111, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 110, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 58, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 57, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 114;   a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 70, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 69, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 119, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 118, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 117;   a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 236, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 235, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 234, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 238, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 37; or   a heavy chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 242, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 241, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 240, and a light chain variable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 245, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 244.   
     
     
         7 . The antibody, or antigen binding portion thereof, of  claim 1 , wherein the antibody, or antigen binding portion thereof, comprises:
 a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 5;   a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 17 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 21;   a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 25 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 29;   a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 40 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 44;   a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 32 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 47;   a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 63;   a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 67 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 71;   a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 73 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77;   a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 79 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 82;   a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 84 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 88;   a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 90 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 94;   a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 96 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 100;   a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 104 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 108;   a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 109 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 113;   a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 115 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 116;   a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 233 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 237; or   a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 239 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 243.   
     
     
         8 . An antibody, or antigen-binding portion thereof, that binds to the same epitope as the antibody, or antigen-binding portion thereof, of  claim 1 . 
     
     
         9 . The antibody, or antigen-binding portion thereof, of  claim 1 , wherein the antibody or antibody binding portion thereof does not bind to SEZ6 or SEZ6L. 
     
     
         10 . An isolated nucleic acid encoding an antibody, or antigen binding portion thereof, of  claim 1 . 
     
     
         11 . A pharmaceutical composition comprising the antibody, or antigen binding portion thereof, of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         12 . An antibody, or antigen binding portion thereof, of  claim 1 , conjugated to at least one drug. 
     
     
         13 . The antibody, or antigen binding portion thereof, of  claim 12 , wherein the at least one drug is selected from the group consisting of an anti-apoptotic agent, a mitotic inhibitor, an anti-tumor antibiotic, an immunomodulating agent, a nucleic acid for gene therapy, an anti-angiogenic agent, an anti-metabolite, a boron-containing agent, a chemoprotective agent, a hormone agent, an anti-hormone agent, a corticosteroid, a photoactive therapeutic agent, an oligonucleotide, a radionuclide agent, a radiosensitizer, a topoisomerase inhibitor, and a tyrosine kinase inhibitor. 
     
     
         14 .- 17 . (canceled) 
     
     
         18 . The antibody, or antigen binding portion thereof, of  claim 12 , wherein the at least one drug is conjugated to the antibody, or antigen-binding portion thereof, via a linker, wherein the linker is cleavable or non-cleavable. 
     
     
         19 .- 20 . (canceled) 
     
     
         21 . The antibody, or antigen binding portion thereof, of  claim 18 , wherein the linker is maleimido-caproyl-valine-citrulline (MC-VC). 
     
     
         22 .- 37 . (canceled) 
     
     
         38 . A method for treating a subject having a SEZ6L2 associated disorder, the method comprising administering an effective amount of an anti-SEZ6L2 antibody, or antigen binding portion thereof, of  claim 1  to the subject, thereby treating the subject having the SEZ6L2 associated disorder. 
     
     
         39 . The method of  claim 38 , wherein the SEZ6L2 associated disease is cancer. 
     
     
         40 . The method of  claim 39 , wherein the cancer is selected from the group consisting of small cell lung cancer, prostate cancer, and neuroendocrine tumors. 
     
     
         41 . The method of  claim 40 , wherein the cancer is characterized as having SEZ6L2 overexpression. 
     
     
         42 .- 49 . (canceled) 
     
     
         50 . A method for inhibiting or decreasing solid tumor growth in a subject having a solid tumor, said method comprising administering an effective amount of the anti-SEZ6L2 antibody, or antigen binding portion thereof, of  claim 1  to the subject having the solid tumor, such that the solid tumor growth is inhibited or decreased. 
     
     
         51 .- 53 . (canceled) 
     
     
         54 . The method of  claim 50 , wherein the anti-SEZ6L2 antibody, or antigen binding portion thereof, or the pharmaceutical composition is administered in combination with an additional agent or an additional therapy. 
     
     
         55 . The method of  claim 54 , wherein the additional therapy is radiation a chemotherapeutic agent, or a PARP inhibitor. 
     
     
         56 .- 59 . (canceled) 
     
     
         60 . The method of  claim 54 , wherein the antibody, or antigen binding portion thereof is an IgG1 antibody. 
     
     
         61 .- 64 . (canceled) 
     
     
         65 . The antibody, or antigen binding portion thereof, of  claim 1 , where the antibody, or antigen binding portion thereof, comprises:
 a heavy chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 5;   a heavy chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 17 and a light chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 21;   a heavy chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 25 and a light chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 29;   a heavy chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 40 and a light chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 44;   a heavy chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 32 and a light chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 47;   a heavy chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 59 and a light chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 63;   a heavy chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 67 and a light chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 71;   a heavy chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 73 and a light chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 77;   a heavy chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 79 and a light chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 82;   a heavy chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 84 and a light chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 88;   a heavy chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 90 and a light chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 94;   a heavy chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 96 and a light chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 100;   a heavy chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 104 and a light chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 108;   a heavy chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 109 and a light chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 113;   a heavy chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 115 and a light chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 116;   a heavy chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 233 and a light chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 237; or   a heavy chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 239 and a light chain variable region comprising the amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 243.