Human neuregulin-1 (NRG-1) recombinant fusion protein compositions and methods of use thereof
The present invention relates to a recombinant fusion protein comprising a fragment of the cardioprotective protein neuregulin-1 (NRG-1) fused to a monoclonal antibody (mAb) backbone and to a method of treating a disease or condition in a subject in need thereof comprising administering a therapeutically effective amount of the recombinant fusion protein or the pharmaceutical composition comprising the recombinant fusion protein disclosed herein.
1. A method of treating a cardiovascular disease or condition in a subject, comprising administering between 0.1 mcg/kg and 5 mg/kg of 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 an active fragment.
3. The method of claim 2 , wherein the active protein fragment of NRG-1 comprises the active domain of NRG-1.
4. The method of claim 1 , wherein the NRG-1 fragment comprises the ERBB3/4 binding domain.
5. The method of claim 1 , wherein the NRG-1 fragment binds to and induces signaling through ErbB4 (HER4).
6. The method of claim 5 , wherein the mAb inhibits NRG-1 signaling through ErbB3 (HER3).
7. The method of claim 1 , wherein said NRG-1 fragment comprises the NRG-1 ß2a isoform.
8. The method 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.
9. The method of claim 8 , 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.
10. The method of claim 1 , wherein the C-terminus of the antibody heavy chain comprises the Fc domain of the antibody.
11. The method of claim 1 , wherein the monoclonal antibody is glycosylated.
12. The method of claim 11 , wherein the glycosylation is N-glycosylation, O-glycosylation or a combination thereof.
13. The method of claim 1 , wherein the NRG-1 fragment comprises the amino acid sequence of SEQ ID NO: 4.
14. The method of claim 1 , wherein the mAb comprises a heavy chain amino acid sequence of SEQ ID NO: 2.
15. The method of claim 1 , wherein the mAb comprises a light chain amino acid sequence of SEQ ID NO: 3.
16. The method of claim 14 , wherein the mature mAb comprises a substitution mutation in at least one of amino acids 234, 239 and 434 of SEQ ID NO: 2.
17. The method of claim 16 , wherein the at least one substitution mutation comprises a L234F mutation, a S239A mutation, a N434A mutation, or a combination thereof.
18. The method of claim 1 , wherein the recombinant fusion protein comprises the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 14.
19. The method of claim 1 , wherein the recombinant fusion protein attenuates proliferation of tumor or cancer cells relative to recombinant NRG-1.
20. The method of claim 1 , wherein administering the recombinant fusion protein alleviates a sign or a symptom of the cardiovascular disease or condition in the subject.
21. The method of claim 1 , wherein administering the recombinant fusion protein treats or delays heart failure.
22. The method of claim 1 , wherein the recombinant fusion protein promotes proliferation, differentiation and survival of cardiomyocytes or cardiac tissue in the subject.
23. The method of claim 1 , wherein the recombinant fusion protein promotes proliferation, differentiation and survival of central nervous system (CNS) cells of the subject.
24. The method of claim 1 , wherein the recombinant fusion protein has a reduced capacity to induce antibody-dependent cell cytotoxicity (ADCC).
25. The method 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.
26. The method of claim 1 , wherein the cardiovascular disease or condition comprises heart failure with preserved ejection fraction, 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.
27. The method of claim 26 , wherein the chemotherapy-induced cardiotoxicity results from a subject receiving anthracyclines, alkylating agents, antimicrotubule agents, or antimetabolite agents used as chemotherapy.
28. The method of claim 1 , wherein the cardiovascular condition is cardiotoxicity as a result of a subject receiving a cancer therapy.
29. The method of claim 28 , wherein the cancer therapy is a HER-2 targeted therapy.
30. The method of claim 29 , 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.
31. The method of claim 1 , comprising intravenous infusion of the recombinant fusion protein.
32. The method of claim 1 , wherein the recombinant fusion protein is formulated in a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent or excipient.
33. A recombinant nucleic acid encoding the recombinant fusion protein of claim 1 .
34. The recombinant nucleic acid of claim 33 , wherein a heavy chain of the mAb is encoded by SEQ ID NO: 6 or SEQ ID NO: 7.
35. The recombinant nucleic acid of claim 33 , wherein a light chain of the mAb is encoded by SEQ ID NO: 8.