Human neuregulin-1 (NRG-1) recombinant fusion protein compositions and methods of use thereof

1. A recombinant fusion protein comprising a fragment of the cardioprotective protein neuregulin-1 (NRG-1) fused to a monospecific ErbB3 (HER3) monoclonal antibody (mAb).

2. The recombinant fusion protein of claim 1 , wherein the NRG-1 fragment comprises the ERBB3/4 binding domain.

3. The recombinant fusion protein of claim 1 , wherein said NRG-1 fragment comprises the NRG-1 β2a isoform.

4. The recombinant fusion protein of claim 1 , wherein the recombinant fusion protein comprises the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 14.

5. The recombinant fusion protein of claim 1 , wherein the recombinant fusion protein attenuates proliferation of tumor or cancer cells relative to recombinant NRG-1.

6. The recombinant fusion protein of claim 1 , wherein the recombinant fusion protein promotes cardiomyocyte proliferation, differentiation, and survival.

7. The recombinant fusion protein of claim 1 , wherein the recombinant fusion protein promotes proliferation, differentiation and survival of cardiac tissue.

8. The recombinant fusion protein of claim 1 , wherein the recombinant fusion protein promotes proliferation, differentiation and survival of central nervous system (CNS) cells.

9. The recombinant fusion protein-of claim 1 , wherein the recombinant fusion protein has a reduced capacity to induce antibody-dependent cell cytotoxicity (ADCC).

10. The recombinant fusion protein of claim 1 , wherein the recombinant fusion protein promotes HER2/4 signaling over HER2/3 signaling relative to the signal induction potential of recombinant NRG-1.

11. The recombinant fusion protein of claim 1 , wherein the NRG-1 fragment comprises an active fragment.

12. The recombinant fusion protein of claim 11 , wherein the active protein fragment of NRG-1 comprises the active domain of NRG-1.

13. The recombinant fusion protein-of claim 1 , wherein the NRG-1 fragment binds to and induces signaling through ErbB4 (HER4).

14. The recombinant fusion protein of claim 13 , wherein the mAb inhibits NRG-1 signaling through ErbB3 (HER3).

15. The recombinant fusion protein of claim 1 , wherein the NRG-1 fragment is fused via its N-terminal amino acid to the C-terminus of the antibody heavy chain using a linker.

16. The recombinant fusion protein of claim 15 , wherein said linker comprises at least one copy of a Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser linker set forth in SEQ ID NO: 5.

17. The recombinant fusion protein of claim 15 , wherein the C-terminus of the antibody heavy chain comprises the Fc domain of the antibody.

18. The recombinant fusion protein of claim 1 , wherein the monoclonal antibody is glycosylated.

19. The recombinant fusion protein of claim 18 , wherein the glycosylation is N-glycosylation.

20. The recombinant fusion protein of claim 18 , wherein the glycosylation is 0-glycosylation.

21. The recombinant fusion protein of claim 1 wherein the NRG-1 fragment comprises the amino acid sequence of SEQ ID NO: 4.

22. The recombinant fusion protein of claim 1 , wherein the mAb comprises a heavy chain amino acid sequence of SEQ ID NO: 2.

23. The recombinant fusion protein of claim 22 , wherein the mature mAb comprises a substitution mutation in at least one of amino acids 234, 239 and 434 of SEQ ID NO: 2.

24. The recombinant fusion protein of claim 23 , wherein the at least one substitution mutation comprises a L234F mutation, a S239A mutation, a N434A mutation, or a combination thereof.

25. The recombinant fusion protein of claim 1 , wherein the mAb comprises a light chain amino acid sequence of SEQ ID NO: 3.

26. A kit, comprising an effective amount of the recombinant protein of claim 1 .

27. A pharmaceutical composition comprising the recombinant fusion protein of claim 1 .

28. A method of inhibiting, suppressing or delaying the onset of a cardiovascular disease or condition in a subject, the method comprising administering an effective amount of the pharmaceutical composition of claim 27 .

29. A method of treating a cardiovascular disease or condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 27 .

30. The method of claim 29 , wherein the treatment alleviates a sign or a symptom of the cardiovascular disease or condition in the subject.

31. The method of claim 29 , wherein the cardiovascular disease or condition is Chronic heart failure/Congestive heart failure (CHF), Acute heart failure/Myocardial infarction (MI), Left ventricular systolic dysfunction, Reperfusion injury associated with MI, Chemotherapy-induced cardiotoxicity (adult or pediatric), Radiation-induced cardiotoxicity, or Adjunct to surgical intervention in pediatric congenital heart disease.

32. The method of claim 31 , wherein the chemotherapy-induced cardiotoxicity results from a subject receiving anthracyclines, alkylating agents, antimicrotubule agents, or antimetabolites agents used as chemotherapy.

33. The method of claim 29 , wherein the cardiovascular condition is cardiotoxicity as a result of a subject receiving a cancer therapy.

34. The method of claim 33 , wherein the cancer therapy is a HER-2 targeted therapy.

35. The method of claim 34 , wherein the HER-2 targeted therapy comprises use of trastuzumab, ado-trastuzumab, emtansine, lapatinib, neratinib, pertuzumab, any anti-HER2 antibody, any anti-HER2 agent, or a combination thereof.

36. A recombinant nucleic acid molecule encoding the recombinant fusion protein of claim 1 .

37. A recombinant vector comprising the nucleic acid molecule of claim 36 .

38. A recombinant cell comprising the recombinant vector of claim 37 .