Bifunctional antagonists of activin and tumor necrosis factor alpha and uses thereof
This invention disclosure provides novel bifunctional antagonistic polypeptides comprising at least one TNF-α binding domain and at least one Activin-binding domain, which are highly capable of sequestering TNF-α and Activin or Activin-related ligand in parallel. Also provided are pharmaceutical compositions of such bifunctional polypeptide antagonists and their uses to treat various complex disease conditions, whose pathogenesis involve the activation of both TNF-α-mediated NF-κB signaling pathway and Activin-mediated Smad2/3 signaling pathway.
1 . An isolated bifunctional antagonist molecule comprising a first molecule that is an antibody specifically binding to TNF-α and a second molecule that is a polypeptide specifically binding to an Activin or Activin-related ligand, wherein the bifunctional antagonist molecule simultaneously neutralizes TNF-α signaling and Activin signaling in a potent manner; and wherein the bifunctional molecule comprises the heavy chain amino acid sequence set forth in SEQ ID NO: 39 and the light chain amino acid sequence set forth in SEQ ID NO: 17.
2 . A pharmaceutical composition comprising a therapeutically effective amount of the bifunctional antagonist molecule of claim 1 in admixture with a pharmaceutically acceptable carrier.
3 . A method of treating pulmonary hypertension in a subject, comprising administering to said subject a therapeutically effective amount of the composition of claim 2 .
4 . An isolated nucleic acid molecule comprising a polynucleotide encoding a bifunctional antagonist molecule according to claim 1 .
5 . A recombinant vector comprising the nucleic acid molecule of claim 4 .
6 . A host cell comprising the recombinant vector of claim 5 .
7 . A method for producing a bifunctional antagonist molecule according to claim 1 , comprising the steps of: a) transforming a host cell with a vector comprising a nucleic acid molecule encoding said bifunctional antagonist molecule, b) culturing the host cell under conditions suitable for the expression of the bifunctional antagonist molecule, and c) recovering the bifunctional antagonist molecule from the culture.