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.

1 . An isolated nucleic acid comprising a full-length polynucleotide selected from the group consisting of:
 a) a polynucleotide as defined in SEQ ID NO:3;   b) a polynucleotide as defined in SEQ ID NO:5;   c) a polynucleotide encoding a polypeptide as defined in SEQ ID NO:4;   d) a polynucleotide encoding a polypeptide as defined in SEQ ID NO:6; and   e) a polynucleotide complementary to a full-length polynucleotide of any one of a) through d) above.   
     
     
         2 . An isolated nucleic acid comprising a full-length polynucleotide encoding a polypeptide having at least 80% sequence identity with a polypeptide as defined in SEQ ID NO:4 or SEQ ID NO:6, and wherein said polypeptide interacts with VEGF and/or VEGFR-2. 
     
     
         3 . The nucleic acid of  claim 2 , wherein said interaction of the polypeptide with VEGF and/or VEGFR-2 decreases the activity of VEGF and/or VEGFR-2. 
     
     
         4 - 29 . (canceled) 
     
     
         30 . A method of inhibiting angiogenesis in a biological sample, comprising:
 a) providing a biological sample; and   b) combining the sample with a angiogenesis-inhibiting amount of an intraceptor that decreases activity of VEGF and/or a VEGF-R, wherein comprises 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.   
     
     
         31 . The method of  claim 30 , 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.   
     
     
         32 . The method of  claim 30 , wherein said portion of SEQ ID NO:13 comprises amino acids 1-305 of SEQ ID NO:6. 
     
     
         33 . The method of  claim 30 , wherein said portion of SEQ ID NO:13 comprises amino acids 1-211 of SEQ ID NO:4. 
     
     
         34 . The method of  claim 30 , 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. 
     
     
         35 . The method of  claim 34 , wherein said endoplasmic reticulum signal retention peptide is SEQ ID NO:1. 
     
     
         36 . The method of  claim 30 , wherein the VEGFR is VEGFR-2. 
     
     
         37 . The method of  claim 30 , wherein the intraceptor comprises a polypeptide as defined in SEQ ID NO:4. 
     
     
         38 . The method of  claim 30 , wherein the intraceptor comprises a polypeptide as defined in SEQ ID NO:6. 
     
     
         39 . The method of  claim 30 , wherein the intraceptor comprises a polypeptide having at least 90% sequence identity with the polypeptide as defined in SEQ ID NO:4, or SEQ ID NO:6. 
     
     
         40 . The method of  claim 30 , wherein the intraceptor comprises a polypeptide having at least 80% sequence identity with the polypeptide as defined in SEQ ID NO:4. 
     
     
         41 . The method of  claim 30 , wherein the intraceptor comprises a polypeptide having at least 80% sequence identity with the polypeptide as defined in SEQ ID NO:6. 
     
     
         42 . The method of  claim 30 , wherein the composition comprises a pharmaceutically acceptable carrier. 
     
     
         43 . The method of  claim 30 , wherein the biological sample is from a mammal. 
     
     
         44 . The method of  claim 30 , wherein the biological sample is a human biological sample. 
     
     
         45 . The method of  claim 30 , wherein the biological sample is in a patient and wherein the patient has an angiogenesis-related condition. 
     
     
         46 . The method of  claim 45 , wherein the disease or condition is selected from the group consisting of inflammation, stroke, hemangioma, solid tumors, leukemias, lymphomas, myelomas, metastasis, telangiectasia psoriasis scleroderma, 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 adenomyosis, ovarian hyperstimulation syndrome, ovarian carcinoma, melanoma, venous ulcers, acne, rosacea, warts, eczema, neurofibromatosis, tuberous sclerosis, and chronic inflammatory disease. 
     
     
         47 . The method of  claim 45 , wherein the disease or condition is selected from the group consisting of melanoma, diabetic retinopathy, and macular degeneration. 
     
     
         48 - 53 . (canceled)