Angiogenesis-inhibiting chimeric proteins and the use

Abstract

The present invention is directed to DNA sequence encoding angionenesis-inhibiting recombinant chimeric protein, the chimeric protein per se, the pharmaceutical use of the chimeric protein, and to the pharmaceutical composition containing the recombinant protein and the formulation thereof.

1 . A type of chimeric proteins consisting of different fragments of the VEGF receptors FLT-1 and KDR, characterized in that the chimeric proteins are selected from the following groups :
 a. consisting of the 2 nd  Ig-like domain of FLT-1, and the 3 rd  and the 4 th  Ig-like domains of KDR, designated as FLTd2-KDRd3,4;   b. consisting of the 2 nd  Ig-like domain of FLT-1, the 3 rd  Ig-like domain of KDR, and the 4 th  Ig-like domain of FLT-1, designated as FLTd2-KDRd3-FLTd4;   c. consisting of the 2 nd  Ig-like domain of FLT-1, and the  3   rd , the 4 th  and the 5 th  Ig-like domains of KDR, designated as FLTd2-KDRd3,4,5;   d. consisting of the 2 nd  Ig-like domain of FLT-1, the 3 rd  Ig-like domain of KDR, and the 4 th  and the 5 th  Ig-like domains of FLT-1, designated as FLTd2-KDRd3-FLTd4,5.   
     
     
         2 . A type of chimeric proteins consisting of the chimeric proteins of  claim 1  and human immunoglobulin Fe, which are selected from the following groups:
 FP4′ designated as FLTd2-KDRd3-FLTd4-Fc;   FP5′ designated as FLTd2-KDRd3,4,5-Fc;   FP6′ designated as FLTd2-KDRd3-FLTd4,5-Fc.   
     
     
         3 . The chimeric proteins of  claim 2 , wherein the immunoglobulin Fc is derived from classes or subclasses of human immunoglobulin. 
     
     
         4 . The chimeric proteins of  claim 3 , wherein the immunoglobulin Fc fragment is a full length Fc or a fragment of Fc sequence. 
     
     
         5 . An isolated recombinant DNA coding sequence encoding a chimeric protein, comprising fragments of the VEGF receptors FLT-1 and KDR, and optionally Immunoglobulin Fc, wherein the chimeric protein is selected from the group consisting of:
 a. a chimeric protein consisting of the 2 nd  Ig-like domain of FLT-1, and the 3 rd  and 4 th  Ig-like domains of KDR, designated as FLTd2-KDRd3,4;   b. a chimeric protein consisting of the 2 nd  Ig-like domain of FLT-1, the 3 rd  Ig-like domain of KDR, and the 4 th  Ig-like domain of FLT-1, designated as FLTd2-KDRd3-FLTd4;   c. a chimeric protein consisting of the 2 nd  Ig-like domain of FLT-1, and the 3 rd , 4 th  and 5 th  Ig-like domains of KDR, designated as FLTd2-KDRd3,4,5;   d. a chimeric protein consisting of the 2 nd  Ig-like domain of FLT-1, the 3 rd  Ig-like domain of KDR, and the 4 th  and the 5 th  Ig-like domains of FLT-1, designated as FLTd2-KDRd3 -FLTd4, 5;   e. FP4′ designated as FLTd2-KDRd3-FLTd4-Fc;   f. FP5′ designated as FLTd2-KDRd3-FLTd4-Fc; and   g. FP6′ designated as FLTd2-KDRd3-FLTd4,5-Fc.   
     
     
         6 . An isolated recombinant vector comprising the recombinant DNA sequences of  claim 5 , wherein the vector is selected from plasmid, virus, or DNA fragment. 
     
     
         7 . An isolated recombinant host cell containing the recombinant vector of  claim 6 , wherein the host cell is a eukaryotic cell or prokaryotic cell. 
     
     
         8 . A pharmaceutical composition which comprises one or more chemeric proteins encoded by the recombinant DNA according to  claim 5  and a pharmaceutical acceptable carrier. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the pharmaceutical composition is an injection solution. 
     
     
         10 . A method of treating an angiogenesis-related disease in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to  claim 8 , wherein the disease is selected from the group consisting of a tumor, a diabetic retinopathies, arthritis, anemia and endometrial hyperplasia.