POLYPEPTIDES FOR INHIBITING COMPLEMENT ACTIVATION

• US 20190300589A1
• Filed: 12/23/2016
• Published: 10/03/2019
• Est. Priority Date: 12/23/2015
• Status: Active Grant

• Current Assignee: Greenovation Biotech GmbH
• Original Assignee: Greenovation Biotech GmbH
• Inventors: MICHELFELDER, Stefan, HAFFNER, Karsten
• Granted Patent: US 10,640,540 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/472 Complement proteins, e.g. anaphylatoxin, C3a, C5a
• CPC Class Codes: C07K 2319/70 containing domain for protein-protein interaction
• CPC Class Codes: C07K 2319/74 containing a fusion for binding to a cell surface receptor

Abstract

The invention relates to a polypeptide comprising a C3 convertase effector domain, a C5 convertase effector domain and optionally a terminal complex inhibitory effector domain which is resistant to deregulation by physiologic FHR-Proteins and has a dimerization motif, and to its therapeutic use.

Claims

1. A polypeptide comprising an inhibitory C3 convertase effector domain and an inhibitory C5 convertase effector domain.

2. The polypeptide of claim 1, wherein said inhibitory C3 convertase effector domain confers C3 convertase inhibition by decay-accelerating and cofactor activity.

3. The polypeptide of claim 1, wherein said polypeptide has decay-accelerating and cofactor activity.

4. The polypeptide of claim 1, wherein said inhibitory C3 convertase effector domain is a fragment of Factor H (FH).

5. The polypeptide of claim 1, wherein said inhibitory C3 convertase effector domain comprises or consists of Short Consensus Repeats (SCRs) 1 to 4 of FH.

6. The polypeptide of claim 1, wherein said inhibitory C3 convertase effector domain comprises or consists of SCRs 1-4 of FHR2.

7. The polypeptide of claim 1, wherein said inhibitory C5 convertase effector domain is a fragment of Factor H-related protein 1 (FHR1).

8. The polypeptide of claim 1, wherein said inhibitory C5 convertase effector domain comprises or consists of SCR1 and SCR2 of FHR1.

9. The polypeptide of claim 1, wherein C5 activation and cleavage into C5a and C5b is inhibited by binding of the polypeptide to C5.

10. The polypeptide of claim 1, further comprising a domain that is capable of binding to cellular surfaces.

11. The polypeptide of claim 1, wherein said domain that is capable of binding to cellular surfaces comprises SCR19 and SCR20 of FH.

12. The polypeptide of claim 1, wherein said polypeptide is a multimer.

13. The polypeptide of claim 12, comprising at least one dimerization motif from SCR1 of FHR1.

14. The polypeptide of claim 1, wherein said polypeptide is capable of inhibiting TCC (C5b-9) formation.

15. The polypeptide of claim 14, wherein said TCC formation is inhibited by binding of the polypeptide to C5b-6.

19. A method of treating or preventing a disorder related to or associated with the complement system, which comprises administering to patient in need thereof, the polypeptide as defined in claim 1.

20. The method according to claim 19, wherein said disorder related to or associated with the complement system is selected from the group consisting of atypical hemolytic uremic syndrome (aHUS), thrombotic microangiopathy (TMA), C3 glomerulopathy (C3G), IgA nephropathy, systemic lupus erythematosus nephritis, transplant rejection, paroxysmal nocturnal hemoglobinuria (PNH), age-related macular degeneration (AMD), infectious diseases, sepsis, SIRS, trauma injury, ischemia/reperfusion damage and myocardial infarction.

21. A nucleic acid encoding the polypeptide of claim 1.

22. A plasmid or vector comprising the nucleic acid of claim 21.

23. A cell comprising the nucleic acid of claim 21.

24. A method of producing a polypeptide of comprising an inhibitory C3 convertase effector domain and an inhibitory C5 convertase effector domain, which comprises culturing the cells of claim 23 in a culture medium under conditions that allow expression of the polypeptide, and recovering the polypeptide from the cells or the culture medium.

16. A polypeptide having the structure A-B-C, wherein A is an inhibitory C5 convertase effector domain, B is an inhibitory C3 convertase effector domain, and C is absent or a domain that is capable of binding to cellular surfaces.

17. The polypeptide of claim 16, wherein A and B are fused directly or via a linker.

18. The polypeptide of claim 16, wherein B and C are fused directly or via a linker.