Monoclonal Antibodies for Enhancing or Inhibiting Insulin-Like Growth Factor 1 (IGF-1)

Abstract

The present invention provides an antibody or antigen-binding fragment thereof that binds α v β 3 integrin, as well as methods of use in the treatment of diseases and disorders.

1 - 41 . (canceled) 
     
     
         42 . An isolated antibody or antigen-binding fragment thereof that binds α v β 3  integrin, wherein the antibody or antigen-binding fragment thereof comprises light chain complementarity determining region (LCDR) sequences LCDR1 of SEQ ID NO:1, LCDR2 of SEQ ID NO:2, and LCDR3 of SEQ ID NO:3, and heavy chain complementarity determining region (HCDR) sequences HCDR1 of SEQ ID NO:4, HCDR2 of SEQ ID NO:5, and HCDR3 of SEQ ID NO:6. 
     
     
         43 . The isolated antibody or antigen-binding fragment thereof of  claim 42 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) selected from the group consisting of:
 a) a HCVR comprising the amino acid sequence of SEQ ID NO:7 (VH1);   b) a HCVR comprising the amino acid sequence of SEQ ID NO:8 (VH2);   c) a HCVR comprising the amino acid sequence of SEQ ID NO:9 (VH3);   d) a HCVR comprising the amino acid sequence of SEQ ID NO:10 (VH4);   e) a HCVR comprising the amino acid sequence of SEQ ID NO:11 (VH5); and   f) a HCVR comprising the amino acid sequence of SEQ ID NO:12 (VH6).   
     
     
         44 . The isolated antibody or antigen-binding fragment thereof of  claim 42 , wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region (LCVR) selected from the group consisting of:
 a) a LCVR comprising the amino acid sequence of SEQ ID NO:13 (Vκ1);   b) a LCVR comprising the amino acid sequence of SEQ ID NO:14 (Vκ2); and   c) a LCVR comprising the amino acid sequence of SEQ ID NO:15 (Vκ3).   
     
     
         45 . The isolated antibody or antigen-binding fragment thereof of  claim 42 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:7 (VH1), SEQ ID NO:8 (VH2), SEQ ID NO:9 (VH3), SEQ ID NO:10 (VH4), SEQ ID NO:11 (VH5), or SEQ ID NO:12 (VH6) and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:13 (Vκ1), SEQ ID NO:14 (Vκ2), or SEQ ID NO:15 (Vκ3), wherein the HCVR and the LCVR are present in any combination. 
     
     
         46 . The isolated antibody or antigen-binding fragment thereof of  claim 42 , wherein the antibody or antigen binding fragment thereof comprises a light chain selected from the group consisting of:
 a) a light chain comprising the amino acid sequence of SEQ ID NO:16 (Vκ2);   b) a light chain comprising the amino acid sequence of SEQ ID NO:22 (Vκ1); and   c) a light chain comprising the amino acid sequence of SEQ ID NO:23 (Vκ3).   
     
     
         47 . The isolated antibody or antigen-binding fragment thereof of  claim 42 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain selected from the group consisting of:
 a) a heavy chain comprising the amino acid sequence of SEQ ID NO:17 (VH6);   b) a heavy chain comprising the amino acid sequence of SEQ ID NO:24 (VH1);   c) a heavy chain comprising the amino acid sequence of SEQ ID NO:25 (VH2);   d) a heavy chain comprising the amino acid sequence of SEQ ID NO:26 (VH3);   e) a heavy chain comprising the amino acid sequence of SEQ ID NO:27 (VH4); and   f) a heavy chain comprising the amino acid sequence of SEQ ID NO:28 (VH5).   
     
     
         48 . The isolated antibody or antigen-binding fragment thereof of  claim 42 , wherein the antibody or antigen-binding fragment thereof comprises:
 a) a heavy chain comprising the amino acid sequence of SEQ ID NO:12 (VH6) and a light chain comprising the amino acid sequence of SEQ ID NO:14 (Vκ2);   b) a heavy chain comprising the amino acid sequence of SEQ ID NO:11 (VH5) and a light chain comprising the amino acid sequence of SEQ ID NO:14 (Vκ2);   c) a heavy chain comprising the amino acid sequence of SEQ ID NO:17 (VH6) and a light chain comprising the amino acid sequence of SEQ ID NO:16 (Vκ2); or   d) a heavy chain comprising the amino acid sequence of SEQ ID NO:28 (VH5) and a light chain comprising the amino acid sequence of SEQ ID NO:16 (Vκ2).   
     
     
         49 . The isolated antibody or antigen-binding fragment thereof of  claim 42 , wherein the antibody or antigen-binding fragment thereof comprises human antibody framework (FR) and constant region sequences and wherein one or more framework region amino acid residues in a light chain variable region is substituted from the corresponding framework region sequence of a murine antibody comprising the light chain variable region amino acid sequence of SEQ ID NO:18. 
     
     
         50 . The isolated antibody or antigen-binding fragment thereof of  claim 42 , wherein the antibody or antigen-binding fragment thereof comprises human antibody framework (FR) and constant region sequences and wherein one or more framework region amino acid residues in a heavy chain variable region is substituted from the corresponding framework region sequence of a murine antibody comprising the heavy chain variable region amino acid sequence of SEQ ID NO:20. 
     
     
         51 . The isolated antibody or antigen-binding fragment thereof of  claim 42 , wherein the antibody or antigen-binding fragment thereof is conjugated to at least one therapeutic or diagnostic agent. 
     
     
         52 . The isolated antibody or antigen-binding fragment thereof of  claim 51 , wherein the therapeutic agent is selected from the group consisting of a cytotoxic agent, a chemotherapeutic drug, a radionuclide, an immunomodulator, a hormone, an enzyme, an oligonucleotide, a photoactive therapeutic agent and any combination thereof. 
     
     
         53 . A method of treating a disorder associated with aberrant IGF-1 activity in a subject in need thereof, comprising administering to the subject an effective amount of the isolated antibody or antigen-binding fragment thereof of  claim 42 , thereby inhibiting IGF-1 activity in the subject and treating the disorder, wherein the disorder is selected from the group consisting of kidney disease, nephropathy, diabetic kidney disease, renal failure, atherosclerosis, coronary artery disease, peripheral vascular disease, diabetic ulcer, disease of the eye, retinopathy, macular edema, cancer, nerve damage, neuropathy, osteoporosis, pathogenic angiogenesis and any combination thereof. 
     
     
         54 . An isolated nucleic acid molecule selected from the group consisting of:
 a) an isolated nucleic acid molecule encoding an amino acid sequence of  claim 42 ;   b) an isolated nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:35;   c) an isolated nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:34; and   d) an isolated nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:37.   
     
     
         55 . A vector comprising the isolated nucleic acid molecule of  claim 54 . 
     
     
         56 . An isolated or transformed cell comprising the isolated nucleic acid molecule of  claim 54 . 
     
     
         57 . An isolated or transformed cell comprising the vector of  claim 55 . 
     
     
         58 . A method of inhibiting phosphorylation of an αvβ3 integrin, comprising contacting the αvβ3 integrin with an isolated antibody or antigen-binding fragment thereof that binds the αvβ3 integrin cysteine loop (C-loop) domain of SEQ ID NO:29, wherein the antibody or antigen-binding fragment thereof comprises:
 a) a light chain variable region comprising a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO:1, a LCDR2 of SEQ ID NO:2, and a LCDR3 of SEQ ID NO:3, and 
 b) a heavy chain variable region comprising a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO:4, a HCDR2 of SEQ ID NO:5, and a HCDR3 of SEQ ID NO:6, 
 wherein phosphorylation of the αvβ3 integrin is inhibited.