Multifunctional protein molecules comprising decorin and use thereof
The present invention relates to multifunctional protein molecules comprising decorin and uses thereof. In particular, the present invention relates to multifunctional protein molecules comprising decorin and a targeting polypeptide such as an antibody and methods of their production and uses thereof.
1. A multifunctional protein molecule comprising at least one decorin molecule having at least 95% sequence identity to SEQ ID NO:7 linked to an antibody molecule selected from the group consisting of bevacizumab, ranibizumab, ipilimumab, atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab.
2. The multifunctional protein molecule of claim 1 , wherein the decorin molecule comprises a mutation at position 4 as compared to wild-type decorin.
3. The multifunctional protein molecule of claim 2 , wherein the mutation is a serine to alanine mutation.
4. The multifunctional protein molecule of claim 2 , wherein the decorin molecule lacks modification by glycosaminoglycans molecules at position 4 of the decorin molecule.
5. The multifunctional protein molecule of claim 1 , wherein the multifunctional protein molecule comprises two or more copies of the decorin molecule.
6. The multifunctional protein molecule of claim 1 , wherein the decorin molecule comprises a decorin domain or domains that binds a signaling molecule selected from the group consisting of Transforming Growth Factor-β (TGF-β), Connective Tissue Growth Factor (CTGF), Platelet-Derived Growth Factor (PDGF), Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), Hepatocyte Growth Factor Receptor (HGFR), Insulin-like Growth Factor 1 Receptor (IGF-1R), Epidermal Growth Factor Receptors (EGFRs), myostatin and C1q.
7. The multifunctional protein molecule of claim 6 , wherein the TGF-β binding domain comprises amino acids Asp45-Lys359 of full length endogenous human decorin or amino acids Leu155-Va1260 of full length endogenous human decorin.
8. The multifunctional protein molecule of claim 6 , wherein the multifunctional protein molecule comprises two or more copies of the decorin molecule.
9. The multifunctional protein molecule of claim 1 , wherein the decorin molecule is operably linked to a heavy chain of the antibody.
10. The multifunctional protein molecule of claim 1 , wherein the multifunctional protein molecule is a fusion protein.
11. The multifunctional protein molecule of claim 1 , wherein the decorin molecule is chemically linked to the antigen binding protein.
12. A nucleic acid or set of nucleic acids encoding a multifunctional protein molecule of claim 1 .
13. A vector or vectors comprising the nucleic acid or set of nucleic acids of claim 12 .
14. A host cell comprising the vector or vectors of claim 13 .
15. A method of treating a disorder characterized by angiogenesis or tumor growth, comprising:
administering the multifunctional protein molecule of claim 1 to a subject under conditions such that angiogenesis or tumor growth is inhibited in the subject.
16. The method of claim 15 , wherein the tumor is selected from the group consisting of lung cancer, colorectal cancer, liver cancer, breast cancer, kidney cancer, cervical cancer, ovarian cancer, and glioblastoma.