Methods and compositions for pdgf-cc inhibition

Abstract

The present invention relates, in part, to isolated antibodies that specifically interact with and show measurable binding affinity to an epitope of platelet derived growth factor C (PDGF-C). Such antibodies may be used for the modulation of PDGF-C activity in or secreted from a cell to study its effects on cell function and, in certain embodiments, for the treatment and/or prevention of a disease or condition associated with PDGF-C signing pathway.

1 - 63 . (canceled) 
     
     
         64 . A method for treating
 a. a cerebrovascular disease or condition; or   b. a disorder or condition associated with compromised brain blood barrier (BBB);   said method comprising administering to a subject in need thereof an effective amount of an antibody or antigen-binding fragment thereof that specifically interacts and shows measurable affinity to a polypeptide comprising the active portion of PDGF-C (SEQ ID NO: 2) or a polypeptide or a polypeptide having at least 90% sequence identity thereto.   
     
     
         65 . The method of  claim 64 , wherein the cerebrovascular disease or condition is one selected from the group consisting of edema ascites, hydrothorax, hydropericardium, cerebral/brain edema, hydrocephalus, glaucoma, acute pulmonary edema, a retinopathy, a maculopathy, stroke, ischemic retinopathy, diabetic retinopathy, Alzheimer's disease, multiple sclerosis, trauma, inflammation. 
     
     
         66 . The method according to  claim 64 , wherein the condition is cerebral edema, pulmonary embolism, cardiovascular diseases, head trauma, infection, neurological diseases, or other diseases where edema is a significant clinical problem. 
     
     
         67 . The method according to  claim 65 , wherein the cerebral/brain edema is selected from the group consisting of edema ascites, hydrothorax, hydropericardium, hydrocephalus, glaucoma, acute pulmonary edema, anasarca and hydrops. 
     
     
         68 . The method according to  claim 64 , wherein the antibody or antigen-binding fragment thereof is administered in combination with another therapeutic agent. 
     
     
         69 . The method according to  claim 64 , wherein the method comprises sequential administration of the antibody or antigen-binding fragment thereof and another therapeutic agent. 
     
     
         70 . The method according to  claim 64 , wherein the antibody or antigen-binding fragment thereof is administered by delivery to the vascular bed in the area of the blood brain barrier. 
     
     
         71 . The method according to  claim 64 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. light chain complementary determining regions CDR1L, CDR2L, and CDR3L, wherein CDR1L comprises SEQ ID NO: 16 or a sequence having at least 75% sequence identity thereto; CDR2L comprises SEQ ID NO: 17 or a sequence having at least 75% sequence identity thereto, and CDR3L comprises SEQ ID NO: 18 or a sequence having at least 75% sequence identity thereto; and   b. heavy chain complementary determining regions CDR1H, CDR2H, and CDR3H, wherein CDR1H comprises SEQ ID NO: 34 or a sequence having at least 75% sequence identity thereto, CDR2H comprises SEQ ID NO: 35 or a sequence having at least 75% sequence identity thereto, and CDR3H comprises SEQ ID NO: 36 or a sequence having at least 75% identity thereto.   
     
     
         72 . The method according to  claim 64 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. light chain complementary determining regions CDR1L, CDR2L, and CDR3L, wherein CDR1L comprises SEQ ID NO: 16 or a sequence having at least 90% sequence identity thereto; CDR2L comprises SEQ ID NO: 17 or a sequence having at least 90% sequence identity thereto, and CDR3L comprises SEQ ID NO: 18 or a sequence having at least 90% sequence identity thereto; and   b. heavy chain complementary determining regions CDR1H, CDR2H, and CDR3H, wherein CDR1H comprises SEQ ID NO: 34 or a sequence having at least 90% sequence identity thereto, CDR2H comprises SEQ ID NO: 35 or a sequence having at least 75% sequence identity thereto, and CDR3H comprises SEQ ID NO: 36 or a sequence having at least 90% identity thereto.   
     
     
         73 . The method according to  claim 64 , wherein said polypeptide comprises SEQ ID NO: 3. 
     
     
         74 . The method according to  claim 64 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a CDR1L comprising SEQ ID NO: 16; a CDR2L comprising SEQ ID NO: 17; and a CDR3L comprising SEQ ID NO: 18; and   b. a CDR1H comprising SEQ ID NO: 34 or a sequence having at least 90% sequence identity thereto, a CDR2H comprising SEQ ID NO: 35 or a sequence having at least 75% sequence identity thereto, and a CDR3H comprising SEQ ID NO: 36.   
     
     
         75 . The method according to  claim 64 , wherein the antibody or antigen-binding fragment thereof comprises
 a. light chain complementary determining regions CDR1L, CDR2L, and CDR3L, wherein CDR1L comprises SEQ ID NO: 16; CDR2L comprises SEQ ID NO: 17; and CDR3L comprises SEQ ID NO: 18; and   b. heavy chain complementary determining regions CDR1H, CDR2H, and CDR3H, wherein
 i. CDR1H comprises SEQ ID NO: 34, CDR2H comprises SEQ ID NO: 35, and CDR3H comprises SEQ ID NO: 36; or 
 ii. CDR1H comprises SEQ ID NO: 46, CDR2H comprises SEQ ID NO: 47, and CDR3H comprises SEQ ID NO: 48; or 
 iii. CDR1H comprises SEQ ID NO: 49, CDR2L comprises SEQ ID NO: 50, and CDR3H comprises SEQ ID NO: 51. 
   
     
     
         76 . A method of modulating activity of platelet derived growth factor C (PDGF-C) in a cell comprising contacting the cell with an effective amount of the antibody of antibody or antigen-binding fragment thereof that specifically interacts and shows measurable affinity to a polypeptide comprising the active portion of PDGF-C (SEQ ID NO: 2) or a polypeptide or a polypeptide having at least 90% sequence identity thereto. 
     
     
         77 . The method of  claim 76 , wherein the cell is a tumor cell, tumor epithelial cell or tumor stroma cell expressing PDGF-C. 
     
     
         78 . A method of modulating PDGF-C mediated autocrine and/or paracrine signaling of a cell in a mammal comprising administering to the mammal an effective amount of an antibody or antigen-binding fragment thereof that specifically interacts and shows measurable affinity to a polypeptide comprising the active portion of PDGF-C (SEQ ID NO: 2) or a polypeptide or a polypeptide having at least 90% sequence identity thereto. 
     
     
         79 . The method of  claim 78 , wherein the cell is a tumor cell that secretes PDGF-C or PDGF-CC. 
     
     
         80 . The method of  claim 78 , wherein the tumor cell is formed from a cancer cell type selected from the group consisting of cancers of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or central nervous system. 
     
     
         81 . The method of  claim 78 , wherein the tumor cell is formed from a cancer cell type selected from the group consisting of Bladder TCC, Breast IDC, Breast ILC, Colorectal Adenocarcinoma, Glioblastoma Multiforme, Gliosarcoma, Hepatocellular Carcinoma, Lung Adenocarcinoma, Lung SqCC, Metastatic Melanoma, Mesothelioma, Ovarian Adenocarcinoma, Pancreatic Adenocarcinoma, Prostate Adenocarcinoma, Renal Cell Cancer, and Uterine Adenocarcinoma. 
     
     
         82 . The method according to  claim 78 , wherein the antibody or antigen-binding fragment thereof comprises
 a. light chain complementary determining regions CDR1L, CDR2L, and CDR3L, wherein CDR1L comprises SEQ ID NO: 16; CDR2L comprises SEQ ID NO: 17; and CDR3L comprises SEQ ID NO: 18; and   b. heavy chain complementary determining regions CDR1H, CDR2H, and CDR3H, wherein
 i. CDR1H comprises SEQ ID NO: 34, CDR2H comprises SEQ ID NO: 35, and CDR3H comprises SEQ ID NO: 36; or 
 ii. CDR1H comprises SEQ ID NO: 46, CDR2H comprises SEQ ID NO: 47, and CDR3H comprises SEQ ID NO: 48; or 
 iii. CDR1H comprises SEQ ID NO: 49, CDR2L comprises SEQ ID NO: 50, and CDR3H comprises SEQ ID NO: 51. 
   
     
     
         83 . An isolated nucleic acid molecule encoding:
 a. a variable light chain fragment of a monoclonal antibody, wherein the variable light chain fragment comprises light chain complementary determining regions CDR1L, CDR2L, and CDR3L, wherein CDPR1L comprises SEQ ID NO: 16; CDR2L comprises SEQ ID NO: 17, and CDR3L comprises SEQ ID NO: 18; and/or   b. a variable heavy chain fragment of a monoclonal antibody, wherein the variable heavy chain fragment comprises heavy chain complementary determining regions CDR1H, CDR2H, and CDR3H, wherein:
 (i) CDR1H comprises SEQ ID NO: 34, CDR2H comprising comprises SEQ ID NO: 35, and CDR3H comprising comprises SEQ ID NO: 36; or 
 (ii) CDR1H comprises SEQ ID NO: 46, CDR2H comprises SEQ ID NO: 47, and CDR3H comprises SEQ ID NO: 48; or 
 (iii) CDR1H comprises SEQ ID NO: 49, CDR2L comprises SEQ ID NO: 50, and CDR3H comprises SEQ ID NO: 51.