Compositions and Methods for the Intracellular Disruption of VEGF and VEGFR-2 by Intraceptors

Abstract

The present invention provides an intraceptor that interacts with and decreases activity of with VEGF and/or a VEGFR for the treatment of angiogenesis-related conditions. The present invention further provides pharmaceutical compositions, and methods of use thereof for the treatment and prevention of an angiogenesis-related condition using said intraceptors. The invention further provides for nucleic acids encoding said intraceptors.

What is claimed is: 
     
         1 . An intraceptor that interacts with VEGF and/or a VEGFR, said intraceptor comprising a chimeric polypeptide comprising: (a) a portion of SEQ ID NO: 13 operatively linked to a Signal retention peptide, or (b) a polypeptide having at least 80% sequence identity with 30 consecutive amino acids of SEQ ID NO: 13 operatively linked to a signal retention peptide. 
     
     
         2 . The intraceptor of  claim 1 , wherein said portion of SEQ ID NO:13 comprises amino acids 1-305 of SEQ ID NO:6. 
     
     
         3 . The intraceptor of  claim 1 , wherein said portion of SEQ ID NO:13 comprises amino acids 1-211 of SEQ ID NO:4. 
     
     
         4 . The intraceptor of  claim 1 , wherein said VEGFR is selected from the group consisting of VEGFR-1, VEGFR-2 and VEGFR-3. 
     
     
         5 . The intraceptor of  claim 1 , wherein said VEGFR is VEGFR-2. 
     
     
         6 . The intraceptor of  claim 1 , wherein said signal retention peptide prevents secretion of the portion of SEQ ID NO: 13 operatively linked to the retention peptide. 
     
     
         7 . The intraceptor of  claim 1 , wherein said signal retention peptide is an endoplasmic reticulum signal retention peptide. 
     
     
         8 . The intraceptor of  claim 7 , wherein said endoplasmic reticulum signal retention peptide is selected from the group consisting of SEQ ID NO: 1, 7, or 8. 
     
     
         9 . The intraceptor of  claim 7 , wherein said endoplasmic reticulum signal retention peptide is SEQ ID NO:1. 
     
     
         10 . A method for treating an angiogenesis-related condition in a patient, said method comprising:
 contacting a cell of the patient involved in the angiogenesis-related condition with an intraceptor comprising a chimeric polypeptide comprising a portion of SEQ ID NO: 13 operatively linked to a signal retention peptide, or a polypeptide having at least 80% sequence identity with 30 consecutive amino acids of SEQ ID NO: 13 operatively linked to a signal retention peptide, wherein said contact decreases activity of VEGF and/or a VEGFR.   
     
     
         11 . The method of  claim 10 , wherein the intraceptor is selected from the group consisting of:
 a) a polypeptide as defined in SEQ ID NO:4;   b) a polypeptide as defined in SEQ ID NO:6; and   c) a polypeptide having at least 80% sequence identity with the polypeptide of a) through b) above.   
     
     
         12 . The method of  claim 10 , wherein said portion of SEQ ID NO: 13 comprises amino acids 1-305 of SEQ ID NO:6. 
     
     
         13 . The method of  claim 10 , wherein said portion of SEQ ID NO:13 comprises amino acids 1-211 of SEQ ID NO:4. 
     
     
         14 . The method of  claim 10 , wherein said signal retention peptide is an endoplasmic reticulum signal retention peptide selected from the group consisting of SEQ ID NO: 1, 7, or 8. 
     
     
         15 . The method of  claim 14 , wherein said endoplasmic reticulum signal retention peptide is SEQ ID NO: 1. 
     
     
         16 . The method of  claim 10 , wherein the VEGFR is VEGFR-2. 
     
     
         17 . The method of  claim 10 , wherein said angiogenesis-related condition is selected from the group consisting of inflammation, stroke, hemangioma, solid tumors, leukemias, lymphomas, myelomas, metastasis, telangiectasia psoriasis sclerodenna, pyogenic granuloma, myocardial angiogenesis, plaque neovascularization, coronary collaterals, ischemic limb angiogenesis, corneal diseases, rubeosis, neovascular glaucoma, diabetic retinopathy, retrolental fibroplasia, arthritis, diabetic neovascularization, macular degeneration, wound healing, peptic ulcer, fractures, keloids, vasculogenesis, hematopoiesis, ovulation, menstruation, placentation, polycystic ovary syndrome, dysfunctional uterine bleeding, endometrial hyperplasia and carcinoma, endometriosis, failed implantation and subnormal foetal growth, myometrial fibroids (uterine leiomyomas) and adeuomyosis, ovarian hyperstimulation syndrome, ovarian carcinoma, melanoma, venous ulcers, acne, rosacea, warts, eczema, neurofibromatosis, tuberous sclerosis, and chronic inflammatory disease. 
     
     
         18 . The method of  claim 10 , wherein the disease or condition is selected from the group consisting of: melanoma, diabetic retinopathy, and macular degeneration. 
     
     
         19 . The method of  claim 18 , wherein the disease or condition is macular degeneration.