Polypeptides binding to human complement C5
The present invention relates to C5 binding polypeptides, comprising a C5 binding motif, BM, which motif consists of an amino acid sequence selected from i) EX 2 X 3 X 4 A X 6 X 7 EID X 11 LPNL X 16 X 17 X 18 QW X 21 AFIX 25 X 26 LX 28 D, and ii) an amino acid sequence which has at least 86% identity to the sequence defined in i), wherein the polypeptide binds to C5. The present invention moreover relates to C5 binding polypeptides for use in therapy, such as for use in treatment of a C5 related condition, and to methods of treatment.
1. A fusion polypeptide comprising a C5 binding polypeptide, wherein the C5 binding polypeptide comprises a C5 binding motif, BM, which motif consists of an amino acid sequence selected from any one of SEQ ID NO:1-248, wherein said C5 binding motif forms part of two alpha helices with an interconnecting loop, within a three-helix bundle protein domain.
2. The fusion polypeptide according to claim 1 , wherein the BM amino acid sequence is selected from any one of SEQ ID NO:1-12, SEQ ID NO:20, SEQ ID NO:23-24, SEQ ID NO:26-28, SEQ ID NO:32-35, SEQ ID NO:38-39, SEQ ID NO:41, SEQ ID NO:46, SEQ ID NO:49, SEQ ID NO:56-57, SEQ ID NO:59, SEQ ID NO:66, SEQ ID NO:78-79, SEQ ID NO:87, SEQ ID NO:92, SEQ ID NO:106, SEQ ID NO:110, SEQ ID NO:119, SEQ ID NO:125, SEQ ID NO:141, SEQ ID NO:151, SEQ ID NO:161, SEQ ID NO:166, SEQ ID NO:187, SEQ ID NO:197, SEQ ID NO:203, SEQ ID NO:205, SEQ ID NO:215 and SEQ ID NO:243.
3. The fusion polypeptide according to claim 2 , wherein the BM amino acid sequence is selected from any one of SEQ ID NO:1-12.
4. The fusion polypeptide according to claim 3 , wherein the BM amino acid sequence is SEQ ID NO:1 or SEQ ID NO:4.
5. The fusion polypeptide according to claim 1 , in which the three-helix bundle protein domain is selected from domains of Protein A from Staphylococcus aureus and derivatives thereof.
6. The fusion polypeptide according to claim 1 , wherein the C5 binding polypeptide inhibits cleavage of C5.
7. The fusion polypeptide according to claim 1 , wherein the C5 binding polypeptide binds to C5 such that the K D value of the interaction is at most 1×10 −6 M.
8. The fusion polypeptide according to claim 1 , comprising a further polypeptide domain that improves production, purification, stabilization in vivo or in vitro, coupling, or detection of the fusion polypeptide.
9. The fusion polypeptide according to claim 1 , wherein the C5 binding polypeptide is in multimeric form, comprising at least two C5 binding polypeptide monomer units, the amino acid sequences of which may be the same or different.
10. The fusion polypeptide according to claim 9 , wherein the C5 binding polypeptide is in dimeric form.
11. The fusion polypeptide according to claim 1 , comprising a half-life extending moiety which increases the half-life of the C5 binding polypeptide in vivo.
12. The fusion polypeptide according to claim 11 , wherein the half-life extending moiety is an Fc domain.
13. The fusion polypeptide according to claim 1 , wherein the C5 binding polypeptide comprises a C5 binding motif, BM, which motif consists of SEQ ID NO: 1, and wherein the fusion polypeptide further comprises an Fc domain.
14. The fusion polypeptide according to claim 1 , wherein the C5 binding polypeptide comprises a C5 binding motif, BM, which motif consists of SEQ ID NO: 4, and wherein the fusion polypeptide further comprises an Fc domain.
15. A polynucleotide encoding the fusion polypeptide according to claim 1 .
16. A method of treatment of a C5 related condition, comprising administering a fusion polypeptide according to claim 1 .
17. The method of treatment according to claim 16 , wherein the C5 related condition is selected from inflammatory disease; autoimmune disease; infectious disease; cardiovascular disease; neurodegenerative disorders; cancer; graft injury; wounds; eye disease; kidney disease; pulmonary diseases; hematological diseases; allergic diseases and dermatological diseases.
18. The method of treatment according to claim 16 , wherein said C5 related condition is paroxysmal nocturnal hemoglobinuria (PNH).
19. The method of treatment according to claim 16 , wherein said fusion polypeptide is administered intravenously, subcutaneously, by inhalation, nasally, orally, intravitreally, or topically.
20. The fusion polypeptide according to claim 1 , wherein the C5 binding polypeptide binds to C5 such that the K D value of the interaction is at most 1×10 −7 M.
21. The fusion polypeptide according to claim 1 , wherein the C5 binding polypeptide binds C5 such that the K D value of the interaction is at most 1×10 −8 M.
22. The fusion polypeptide according to claim 1 , wherein the C5 binding polypeptide binds C5 such that the K D value of the interaction is at most 1×10 −9 M.