FGFR-FC Fusion Proteins and the Use Thereof

Abstract

The present invention belongs to the field of biotechnology and relates to the treatment of diseases, especially the treatment of FGF overexpression-related diseases. Particularly, the present invention relates to FGFR-Fc fusion proteins and the use thereof in the treatment of angiogenesis regulation-related diseases. More particularly, the present invention relates to isolated soluble FGFR-Fc fusion proteins and their applications in manufacture of the medicament for the treatment of angiogenesis regulation-related diseases.

We claim: 
     
         1 . An isolated soluble fusion protein of fibroblast growth factor receptor (FGFR), comprising: a part derived from an intermediate functional sequence (IFS) of an Ig-like domain of FGFR, a second Ig-like domain (D2) of FGFR, a third Ig-like domain (D3) of FGFR, and an immunoglobulin Fc region. 
     
     
         2 . The fusion protein of  claim 1 , which binds fibroblast growth factor (FGF). 
     
     
         3 . The fusion protein of  claim 1 , wherein the part derived from IFS does not comprise an acidic box (AB). 
     
     
         4 . The fusion protein of  claim 1 , wherein the part derived from IFS comprises the amino acid sequence corresponding to position 134 to position 162, position 145 to position 162, or position 151 to position 162 of SEQ ID NO: 1. 
     
     
         5 . The fusion protein of  claim 1 , further comprising a first Ig-like domain (D1) of FGFR or a moiety thereof. 
     
     
         6 . The fusion protein of  claim 5 , wherein the first Ig-like domain of FGFR or a moiety thereof comprises:
 an amino acid sequence corresponding to position 40 to position 118 of SEQ ID NO: 1, or an amino acid sequence having at least 70% identity with the sequence of position 40 to position 118 of SEQ ID NO: 1; or   an amino acid sequence corresponding to position 77 to position 118 of SEQ ID NO: 1, or an amino acid sequence having at least 70% identity with the amino acid sequence of position 77 to position 118 of SEQ ID NO: 1.   
     
     
         7 . The fusion protein of  claim 1 , wherein
 said D2 domain comprises an amino acid sequence corresponding to position 163 to position 247 of SEQ ID NO: 1, or an amino acid sequence having at least 70% identity with the amino acid sequence of position 163 to position 247 of SEQ ID NO: 1; and/or   said D3 domain comprises an amino acid sequence corresponding to position 270 to position 359 of SEQ ID NO: 1, or an amino acid sequence having at least 70% identity with the amino acid sequence of position 270 to position 359 of SEQ ID NO: 1.   
     
     
         8 . The fusion protein of  claim 1 , wherein the immunoglobulin Fc region is human IgG and comprises:
 an amino acid sequence of SEQ ID NO: 7, or an amino acid sequence having at least 70% identity to the amino acid sequence of SEQ ID NO: 7; or   an amino acid sequence encoded by a nucleotide sequence of SEQ ID NO: 8, or an amino acid sequence encoded by a nucleotide sequence having at least 70% identity with the nucleotide sequence of SEQ ID NO: 8.   
     
     
         9 . The fusion protein of  claim 1 , wherein one or more of the parts, domains and/or regions involved are linked by one or more linkers. 
     
     
         10 . The fusion protein of  claim 1 , which comprises a part derived from an extracellular domain of FGFR and an immunoglobulin Fc region, wherein the part derived from the extracellular domain of FGFR comprises:
 (1) an amino acid sequence corresponding to positions 358-580 of SEQ ID NO: 9, positions 304-526 of SEQ ID NO: 10, positions 278-500 of SEQ ID NO: 11, positions 246-468 of SEQ ID NO: 12, positions 235-457 of SEQ ID NO: 13, positions 229-451 of SEQ ID NO: 14 or positions 224-446 of SEQ ID NO: 15, or is encoded by a nucleotide sequence corresponding to positions 1074-1740 of SEQ ID NO: 16, positions 912-1578 of SEQ ID NO: 17, positions 834-1500 of SEQ ID NO: 18, positions 738-1404 of SEQ ID NO: 19, positions 705-1371 of SEQ ID NO: 20, positions 687-1353 of SEQ ID NO: 21 or positions 672-1338 of SEQ ID NO: 22;   (2) an amino acid sequence having at least 70% identity with the amino acid sequence corresponding to positions 358-580 of SEQ ID NO: 9, positions 304-526 of SEQ ID NO: 10, positions 278-500 of SEQ ID NO: 11, positions 246-468 of SEQ ID NO: 12, positions 235-457 of SEQ ID NO: 13, positions 229-451 of SEQ ID NO: 14 or positions 224-446 of SEQ ID NO: 15; or   (3) an amino acid sequence encoded by a nucleotide sequence having at least 70% identity with a nucleotide sequence corresponding to positions 1074-1740 of SEQ ID NO: 16, positions 912-1578 of SEQ ID NO: 17, positions 834-1500 of SEQ ID NO: 18, positions 738-1404 of SEQ ID NO: 19, positions 705-1371 of SEQ ID NO: 20, positions 687-1353 of SEQ ID NO: 21 or positions 672-1338 of SEQ ID NO: 22.   
     
     
         11 . The Fc fusion protein of  claim 1 , wherein said protein comprises:
 (1) an amino acid sequence indicated by any one of SEQ ID NOs: 9-15, or an amino acid sequence encoded by a nucleotide sequence indicated by any one of SEQ ID NOs: 16-22;   (2) an amino acid sequence having at least 70% identity with an amino acid sequence indicated by any one of SEQ ID NOs: 9-15; or   (3) an amino acid sequence encoded by a nucleotide sequence having at least 70% identity with the nucleotide sequence indicated by any one of SEQ ID NOs: 16-22.   
     
     
         12 . An isolated nucleic acid molecule encoding the fusion protein of  claim 1 . 
     
     
         13 . The nucleic acid molecule of  claim 12 , comprising a nucleotide sequence indicated by any one of SEQ ID NOs: 16-22. 
     
     
         14 . A vector comprising the nucleic acid molecule of  claim 12 . 
     
     
         15 . A cell transfected by the vector of  claim 14 . 
     
     
         16 . A pharmaceutical composition, comprising the fusion protein of  claim 1 , and/or a nucleic acid molecule encoding said fusion protein, as well as a pharmaceutically acceptable carrier. 
     
     
         17 . A method for producing an angiogenesis-inhibitory fusion protein, wherein said method comprises expressing the fusion protein of  claim 1  in a cell. 
     
     
         18 . A method for producing a medicament for the inhibition of angiogenesis, or for the prevention and/or treatment of tumors, wherein said method comprises the use of the fusion protein of  claim 1 , or a nucleic acid molecule encoding said fusion protein. 
     
     
         19 . A method for inhibiting angiogenesis in a subject or for the treatment and/or prevention of a tumor in a subject, wherein said method comprises administering, to a subject in need of such inhibition, prevention, and/or treatment, an effective amount of a fusion protein of  claim 1  and/or a nucleic acid molecule encoding said fusion protein. 
     
     
         20 . A method for binding FGF in vitro or in vivo, which comprises contacting FGF to a fusion protein of  claim 1 .