C3B binding polypeptide
Polypeptides comprising a C3b binding region are disclosed, as well as nucleic acids and vectors encoding such polypeptides, and cells and compositions comprising such polypeptides. Also disclosed are uses and methods using the polypeptides for treating and preventing diseases and conditions.
1. A method of treating or reducing the likelihood of an ocular complement-related disease or condition, the method comprising administering a polypeptide which is capable of binding C3b, the polypeptide comprising an amino acid sequence wherein said amino acid sequence consists of a sequence having at least 85% identity to SEQ ID NO:4 and wherein the polypeptide has a total length of 450 amino acids or fewer.
2. A method according to claim 1 , wherein the treatment or reduction of the likelihood of an ocular disease or condition comprises modifying at least one ocular cell of a subject to express or comprise the polypeptide.
3. A method according to claim 1 , wherein the treatment or reduction of the likelihood of an ocular disease or condition comprises modifying at least one ocular cell of a subject to express or comprise a nucleic acid encoding the polypeptide.
4. A method according to claim 1 , wherein the treatment or reduction of the likelihood of an ocular disease or condition comprises administering a vector comprising a nucleic acid encoding the polypeptide to at least one ocular cell of a subject.
5. A method according to claim 2 , wherein the at least one ocular cell is a retinal pigment epithelial (RPE) cell.
6. A method according to claim 1 , wherein the disease or condition is a disease or condition in which C3b or a C3b-containing complex, an activity/response associated with C3b or a C3b-containing complex, or a product of an activity/response associated with C3b or a C3b-containing complex is pathologically implicated.
7. A method according to claim 1 , wherein the disease or condition is selected from one or more of: macular degeneration, age-related macular degeneration (AMD), early AMD, intermediate AMD, late AMD, geographic atrophy (dry′ AMD), ‘wet’ (neovascular) AMD, choroidal neovascularisation (CNV), glaucoma, autoimmune uveitis, diabetic retinopathy, and early-onset macular degeneration (EOMD).
8. A method according to claim 1 , wherein the polypeptide comprises an amino acid sequence that consists of a sequence having at least 95% identity to SEQ ID NO:4.
9. A method according to claim 1 , wherein Xaa at position 111 of SEQ ID NO:4 is A or T, Xaa at position 157 of SEQ ID NO:4 is P or L, and/or Xaa at position 160 of SEQ ID NO:4 is G or R.
10. A method according to claim 1 , wherein the polypeptide has a total length of 50 to 250 amino acids.
11. A method according to claim 1 , wherein the polypeptide comprises, or consists of, SEQ ID NO:2, SEQ ID NO:3 or SEQ ID NO:13.
12. A method according to claim 1 , wherein the polypeptide is capable of acting as a co-factor for Complement Factor I.
13. A method according to claim 1 , wherein the polypeptide is capable of being expressed functionally by RPE cells and/or is capable of diffusing across Bruch's membrane (BrM).
14. A method according to claim 1 , wherein the polypeptide binds to C3b in the region bound by a co-factor for Complement Factor I, or wherein the polypeptide binds to C3b in the region bound by Complement Receptor 1 (CR1).
15. A method according to claim 1 , wherein the polypeptide comprises a secretory pathway sequence.
16. A method according to claim 15 , wherein the secretory pathway sequence comprises, or consists of, SEQ ID NO:7, or wherein the polypeptide comprises, or consists of, SEQ ID NO:47, 49, or 51.
17. A method according to claim 15 , wherein the polypeptide comprises a cleavage site for removing the secretory pathway sequence.
18. A method according to claim 1 , wherein the treatment or reduction of the likelihood comprises administering a nucleic acid encoding the polypeptide.
19. A method according to claim 18 , wherein the nucleic acid encodes a polypeptide comprising or consisting of SEQ ID NO:2.
20. A method according to claim 18 , wherein the nucleic acid comprises a sequence having at least 95% sequence identity to SEQ ID NO:35.
21. A method according to claim 4 , wherein the vector is a viral vector.
22. A method according to claim 21 , wherein the vector is a lentiviral vector, a retroviral vector, an adenoviral vector, an adeno-associated viral (AAV) vector, a vaccinia virus vector, or a herpesvirus vector.
23. A method according to claim 1 , wherein the polypeptide is functional on the RPE side of Bruch's membrane and in the choroid and/or choriocapillaris.