Fusion polypeptides capable of activating receptors
A fusion polypeptide comprising (A) x -M-(A′) y , wherein A and A′ are each polypeptides capable of binding a target receptor. The fusion polypeptides of the invention form multimeric proteins which activate the target receptor. A and A′ may be each be an antibody or fragment derived from an antibody specific for a target receptor, such as the same or different scFv fragments, and/or a ligand or ligand fragment or derivative capable of binding the target protein, M is a multimerizing component, and X and Y are independently a number between 1-10.
1. A dimer formed from two fusion polypeptides of the form (A)-M-(A′), wherein components A and A′ are each a single chain variable fragment (scFv) antibody capable of binding Tie-2, and component M is a multimerizing component comprising an Fc domain of IgG, said dimer capable of binding to and clustering four or more Tie-2 receptors.
2. The dimer of claim 1 , wherein A and A′ are different scFvs.
3. The dimer of claim 1 , wherein M comprises an Fc domain of human IgG1.
4. A pharmaceutical composition comprising the dimer of claim 1 and a pharmaceutically acceptable carrier.
5. A fusion polypeptide comprising scFv A12A -Fc-scFv B2 (SEQ ID NO: 28).
6. A dimer formed from two fusion polypeptides of claim 5 .
7. A pharmaceutical composition comprising the dimer of claim 6 and a pharmaceutically acceptable carrier.
8. A fusion polypeptide comprising scFv B2 -Fc-scFv B2 (SEQ ID NO: 29).
9. A dimer formed from two fusion polypeptides of claim 8 .
10. A pharmaceutical composition comprising the dimer of claim 9 and a pharmaceutically acceptable carrier.
11. A dimer formed from two fusion polypeptides of the form (A)-M-(A′), wherein component A is a single chain variable fragment (scFv) antibody capable of binding Tie-2, component M is a multimerizing component comprising an Fc domain of IgG, and component A′ is a fibrinogen domain of Ang1 or Ang2, said dimer capable of binding to and clustering four or more Tie-2 receptors.
12. The dimer of claim 11 , wherein A′ is a fibrinogen domain of Ang1.
13. The dimer of claim 11 , wherein A′ is a fibrinogen domain of Ang2.
14. The dimer of claim 11 , wherein M comprises an Fc domain of human IgG1.
15. A fusion polypeptide comprising scFv B2 -Fc-FD1 (SEQ ID NO: 30).
16. A dimer formed from two fusion polypeptides of claim 15 .
17. A pharmaceutical composition comprising the dimer of claim 16 and a pharmaceutically acceptable carrier.
18. A fusion polypeptide comprising scFv B2 -Fc-FD2 (SEQ ID NO: 31).
19. A dimer formed from two fusion polypeptides of claim 18 .
20. A pharmaceutical composition comprising the dimer of claim 19 and a pharmaceutically acceptable carrier.