Treatment of diseases related to hyperactivity of the complement system
Raising the level of Factor I above physiological levels can be used to treat diseases in which the underlying pathology is linked to overactivity of the C3b-feedback cycle and the generation and pro-inflammatory effects of iC3b. Methods, agents, and compositions for treatment of such diseases are described.
1. A method for treating Age-related Macular Degeneration (AMD) or atypical haemolytic uraemic syndrome (aHUS) in a human subject in need thereof, which comprises systemically administering a pharmaceutical composition comprising a therapeutically effective amount of an agent selected from native Factor I and a polypeptide that has at least 90% amino acid identity with native Factor I and that retains C3b-inactivating and iC3b-degradation activity, and does not comprise Factor H, to the human subject, and wherein the therapeutically effective amount of the agent increases the level of C3b-inactivating and iC3b-degradation activity in the plasma of the human subject to a level that exceeds a normal level of C3b-inactivating and iC3b-degradation activity, thereby treating the AMD or aHUS in the human subject.
2. The method of claim 1 , wherein the agent is administered at a dosage of from 6.5 mg to 250 mg.
3. The method of claim 1 , wherein the human subject has a normal level of C3b-inactivating and iC3b-degradation activity provided by the human subject's Factor I.
4. The method of claim 3 , wherein the normal level is in the range 30-40 μg/ml Factor I in the subject's plasma.
5. The method of claim 1 , wherein the level of activity in the human subject's plasma is increased by at least 10% above the normal level.
6. The method of claim 1 , wherein the level of activity in the human subject's plasma is increased by no more than 50%.
7. The method of claim 1 , wherein the systemic administration comprises by intravenous or intramuscular administration of 0.05 to 20 mg/kg of the agent to the subject.
8. The method of claim 1 , wherein the agent is administered at a dosage of from 6.5 mg to less than 50 mg.
9. The method of claim 1 , further comprising determining whether the human subject has a genetic predisposition to the disease or a family history of the disease, and administering appropriate therapy depending on the result of the determination.
10. The method of claim 9 , wherein the genetic predisposition is selected from the group consisting of: a mutation in Factor H that reduces its ability to function as a Factor I cofactor compared with wild-type Factor H; a mutation in Factor H that reduces its binding to C3b compared with wild-type Factor H; homozygous Factor H deficiency; a mutation in membrane cofactor protein (MCP) that reduce its function compared with wild-type MCP; heterozygous Factor I deficiency; a gain-of-function mutation in Factor B; and a C3F allotype.
11. The method of claim 1 wherein the method comprises administering native Factor I.
12. The method of claim 1 wherein the human subject is suffering from Age-related Macular Degeneration.
13. The method of claim 1 wherein the human subject is suffering from atypical haemolytic uraemic syndrome (aHUS).
14. The method of claim 1 wherein the native Factor I is recombinant.
15. The method of claim 1 wherein the pharmaceutical composition comprises from 6.5 mg to 250 mg of native Factor I.
16. The method of claim 1 wherein the administration is intravenous, intraperitoneal, intramuscular, or intradermal administration.
17. A method for treating Age-related Macular Degeneration (AMD) in a human subject in need thereof, which comprises intraocular administration of a pharmaceutical composition comprising 0.001 to 1 mg of an agent selected from native Factor I and a polypeptide that has at least 90% amino acid identity with native Factor I and that retains C3b-inactivating and iC3b-degradation activity, and does not comprise Factor H, wherein the administration increases the level of C3b-inactivating and iC3b-degradation activity in the human subject to a level that exceeds a normal level of C3b-inactivating and iC3b-degradation activity, thereby treating the AMD in the human subject.