Anti-secretogranin iii (scg3) antibodies and uses thereof

Abstract

Antibodies specific for secretogranin III (Scg3) are disclosed. Methods of using the antibodies, antigen-binding fragments thereof, or pharmaceutical compositions comprising the same in the treatment of diseases such as diabetic retinopathy, neovascular age-related macular degeneration, retinopathy of prematurity, and cancer, are also disclosed.

What is claimed: 
     
         1 . An antibody or antigen-binding fragment thereof that cross-blocks a reference antibody from binding to secretogranin III, wherein the reference antibody is selected from the group consisting of an antibody comprising CDRs of SEQ ID NOs: 3-8; an antibody comprising CDRs of SEQ ID NOs: 11-16; an antibody comprising CDRs of SEQ ID NOs: 19-24; an antibody comprising CDRs of SEQ ID NOs: 27, 4, 28, 22, 29, and 24; an antibody comprising CDRs of SEQ ID NOs: 27, 4, 28, 32, 29, and 24; and an antibody comprising CDRs of SEQ ID NOs: 3, 4, 28, 22, 29, and 24. 
     
     
         2 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the reference antibody is selected from the group consisting of an antibody comprising a heavy chain variable region comprising SEQ ID NO: 1 and a light chain variable region comprising SEQ ID NO: 2; an antibody comprising a heavy chain variable region comprising SEQ ID NO: 9 and a light chain variable region comprising SEQ ID NO: 10; an antibody comprising a heavy chain variable region comprising SEQ ID NO: 17 and a light chain variable region comprising SEQ ID NO: 18; an antibody comprising a heavy chain variable region comprising SEQ ID NO: 25 and a light chain variable region comprising SEQ ID NO: 26; an antibody comprising a heavy chain variable region comprising SEQ ID NO: 30 and a light chain variable region comprising SEQ ID NO: 31; an antibody comprising a heavy chain variable region comprising SEQ ID NO: 38 and a light chain variable region comprising SEQ ID NO: 33; and an antibody comprising a heavy chain variable region comprising SEQ ID NO: 34 and a light chain variable region comprising SEQ ID NO: 35. 
     
     
         3 . An antibody or antigen-binding fragment thereof that binds secretogranin III and comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, wherein (a) CDR-H1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 11, 19, and 27; (b) CDR-H2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 12, and 20; (c) CDR-H3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 13, 21, and 28; (d) CDR-L1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 14, 22, and 32; (e) CDR-L2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 15, 23, and 29; and (f) CDR-L3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 16, and 24. 
     
     
         4 . The antibody or antigen-binding fragment thereof of  claim 3 , wherein (a) CDR-H1 comprises SEQ ID NO: 3; (b) CDR-H2 comprises SEQ ID NO: 4; (c) CDR-H3 comprises SEQ ID NO: 5; (d) CDR-L1 comprises SEQ ID NO: 6; (e) CDR-L2 comprises SEQ ID NO: 7; and (f) CDR-L3 comprises SEQ ID NO: 8. 
     
     
         5 . The antibody or antigen-binding fragment thereof of  claim 3 , wherein (a) CDR-H1 comprises SEQ ID NO: 11; (b) CDR-H2 comprises SEQ ID NO: 12; (c) CDR-H3 comprises SEQ ID NO: 13; (d) CDR-L1 comprises SEQ ID NO: 14; (e) CDR-L2 comprises SEQ ID NO: 15; and (f) CDR-L3 comprises SEQ ID NO: 16. 
     
     
         6 . The antibody or antigen-binding fragment thereof of  claim 3 , wherein (a) CDR-H1 comprises SEQ ID NO: 19; (b) CDR-H2 comprises SEQ ID NO: 20; (c) CDR-H3 comprises SEQ ID NO: 21; (d) CDR-L1 comprises SEQ ID NO: 22; (e) CDR-L2 comprises SEQ ID NO: 23; and (f) CDR-L3 comprises SEQ ID NO: 24. 
     
     
         7 . The antibody or antigen-binding fragment thereof of  claim 3 , wherein (a) CDR-H1 comprises SEQ ID NO: 27; (b) CDR-H2 comprises SEQ ID NO: 4; (c) CDR-H3 comprises SEQ ID NO: 28; (d) CDR-L1 comprises SEQ ID NO: 22; (e) CDR-L2 comprises SEQ ID NO: 29; and (f) CDR-L3 comprises SEQ ID NO: 24. 
     
     
         8 . The antibody or antigen-binding fragment thereof of  claim 3 , wherein (a) CDR-H1 comprises SEQ ID NO: 27; (b) CDR-H2 comprises SEQ ID NO: 4; (c) CDR-H3 comprises SEQ ID NO: 28; (d) CDR-L1 comprises SEQ ID NO: 32; (e) CDR-L2 comprises SEQ ID NO: 29; and (f) CDR-L3 comprises SEQ ID NO: 24. 
     
     
         9 . The antibody or antigen-binding fragment thereof of  claim 3 , wherein (a) CDR-H1 comprises SEQ ID NO: 3; (b) CDR-H2 comprises SEQ ID NO: 4; (c) CDR-H3 comprises SEQ ID NO: 28; (d) CDR-L1 comprises SEQ ID NO: 22; (e) CDR-L2 comprises SEQ ID NO: 29; and (f) CDR-L3 comprises SEQ ID NO: 24. 
     
     
         10 . The antibody or antigen-binding fragment thereof of  claim 4 , comprising a heavy chain variable region comprising SEQ ID NO: 1 and a light chain variable region comprising SEQ ID NO: 2. 
     
     
         11 . The antibody or antigen-binding fragment thereof of  claim 5 , comprising a heavy chain variable region comprising SEQ ID NO: 9 and a light chain variable region comprising SEQ ID NO: 10. 
     
     
         12 . The antibody or antigen-binding fragment thereof of  claim 6 , comprising a heavy chain variable region comprising SEQ ID NO: 17 and a light chain variable region comprising SEQ ID NO: 18. 
     
     
         13 . The antibody or antigen-binding fragment thereof of  claim 7 , comprising a heavy chain variable region comprising SEQ ID NO: 25 and a light chain variable region comprising SEQ ID NO: 26. 
     
     
         14 . The antibody or antigen-binding fragment thereof of  claim 8 , comprising a heavy chain variable region comprising SEQ ID NO: 30 and a light chain variable region comprising SEQ ID NO: 31. 
     
     
         15 . The antibody or antigen-binding fragment thereof of  claim 9 , comprising a heavy chain variable region comprising SEQ ID NO: 38 and a light chain variable region comprising SEQ ID NO: 33. 
     
     
         16 . The antibody or antigen-binding fragment thereof of  claim 9 , comprising a heavy chain variable region comprising SEQ ID NO: 34 and a light chain variable region comprising SEQ ID NO: 35. 
     
     
         17 . The antibody or antigen-binding fragment thereof of any of  claims 1 - 9  comprising a heavy chain variable domain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 1, 9, 17, 25, 30, 38, or 34, and comprising a light chain variable region comprising an amino acid sequence at least 90% identical to SEQ ID NO: 2, 10, 18, 26, 31, 33, or 35. 
     
     
         18 . The antibody or antigen-binding fragment of any of  claims 1 - 17 , wherein the antigen-binding fragment is a Fab fragment, a F(ab′)2 fragment, or a single chain variable fragment (scFv). 
     
     
         19 . A nucleic acid encoding the antibody or antigen-binding fragment thereof of any of  claims 1 - 18 . 
     
     
         20 . An expression vector comprising the nucleic acid of  claim 19 . 
     
     
         21 . A host cell transfected with the expression vector of  claim 20 . 
     
     
         22 . A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of any of  claims 1 - 18  and a physiologically acceptable diluent, excipient or carrier. 
     
     
         23 . A kit comprising the antibody or antigen-binding fragment thereof of any of  claims 1 - 18  or the pharmaceutical composition of  claim 22 . 
     
     
         24 . A method of treating neovascular age-related macular degeneration in a subject in need thereof comprising administering a therapeutically effective amount of the antibody or antigen-binding fragment thereof of any of  claims 1 - 18  or the pharmaceutical composition of  claim 22 . 
     
     
         25 . The method of  claim 24 , wherein the antibody or antigen-binding fragment thereof or pharmaceutical composition is administered in an amount effective to inhibit choroidal neovascularization or polypoidal choroidal vasculopathy. 
     
     
         26 . A method of treating diabetic retinopathy in a subject in need thereof comprising administering a therapeutically effective amount of the antibody or antigen-binding fragment thereof of any of  claims 1 - 18  or the pharmaceutical composition of  claim 22 . 
     
     
         27 . A method of treating retinopathy of prematurity in a subject in need thereof comprising administering a therapeutically effective amount of the antibody or antigen-binding fragment thereof of any of  claims 1 - 18  or the pharmaceutical composition of  claim 22 . 
     
     
         28 . A method of treating an angiogenesis-related disease in the eye, optionally selected from neovascular glaucoma, corneal neovascularization, pterygium, retinal vein occlusions, retinal and macular neovascularization from myopia, inflammatory condition, inherited retinal dystrophies, and sickle cell retinopathy, in a subject in need thereof comprising administering a therapeutically effective amount of the antibody or antigen-binding fragment thereof of any of  claims 1 - 18  or the pharmaceutical composition of  claim 22 . 
     
     
         29 . The method of any of  claims 26 - 28 , wherein the antibody or antigen-binding fragment thereof or pharmaceutical composition is administered in an amount effective to decrease retinal vascular leakage. 
     
     
         30 . The method of any of  claims 26 - 29 , wherein the antibody or antigen-binding fragment thereof or pharmaceutical composition is administered in an amount effective to decrease retinal or choroidal neovascularization. 
     
     
         31 . The method of any of  claims 24 - 30 , wherein the antibody or antigen-binding fragment thereof or pharmaceutical composition is administered intravitreally. 
     
     
         32 . A method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of the antibody or antigen-binding fragment thereof of any of  claims 1 - 18  or the pharmaceutical composition of  claim 22 . 
     
     
         33 . The method of  claim 32 , wherein the subject has a cancer selected from bladder cancer, breast cancer, colorectal cancer, endometrial cancer, eye cancer, kidney cancer, leukemia, lung cancer, lymphoma, pancreatic cancer, prostate cancer, skin cancer, brain cancer, thyroid cancer, liver cancer, oral cancer, oropharyngeal cancer, esophageal cancer, or stomach cancer. 
     
     
         34 . The method of  claim 33 . wherein the subject has an eye cancer selected from retinoblastoma, uveal melanoma, and intraocular lymphoma. 
     
     
         35 . The method of any of  claims 24 - 34 , wherein the antibody or antigen-binding fragment thereof or pharmaceutical composition is administered in an amount effective to inhibit cell proliferation. 
     
     
         36 . A method of treating an angiogenesis-related disease, optionally selected from arthritis, synovitis, osteomyelitis, osteophyte formation, multiple sclerosis, vascular malformations, autoimmune diseases, atherosclerosis, transplant arteriopathy, obesity, psoriasis, warts, allergic dermatitis, scar keloids, pyogenic granulomas, blistering disease, Kaposi sarcoma in AIDS patients, primary pulmonary hypertension, asthma, nasal polyps, inflammatory bowel disease, periodontal disease, liver cirrhosis, ascites, peritoneal adhesions, endometriosis, uterine bleeding, ovarian cysts, ovarian hyperstimulation, restenosis, and cystic fibrosis, in a subject in need thereof comprising administering a therapeutically effective amount of the antibody or antigen-binding fragment thereof of any of  claims 1 - 18  or the pharmaceutical composition of  claim 22 . 
     
     
         37 . The method of any of  claims 24 - 36 , wherein the antibody or antigen-binding fragment thereof is administered in an amount from about 5 μg/kg to about 400 mg/kg body weight of the subject. 
     
     
         38 . The method of any of  claims 24 - 36 , wherein the antibody or antigen-binding fragment thereof is administered to the eye of the subject in an amount from about 0.05 mg to about 10 mg. 
     
     
         39 . Use of the antibody or antigen-binding fragment thereof of any one of  claims 1 - 16  for treating neovascular age-related macular degeneration in a subject in need thereof; treating diabetic retinopathy in a subject in need thereof; or treating retinopathy of prematurity in a subject in need; treating an angiogenesis-related disease in the eye, optionally selected from neovascular glaucoma, corneal neovascularization, pterygium, retinal vein occlusions, retinal and macular neovascularization from myopia, inflammatory condition, inherited retinal dystrophies, and sickle cell retinopathy, in a subject in need thereof.