Treatment of diseases related to hyperactivity of the complement system

Patent metadata

Field	Value
Publication number	US-9782460-B2
Application number	US-201514753193-A
Country	US
Kind code	B2
Filing date	Jun 29, 2015
Priority date	Mar 13, 2009
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

Abstract

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.

First claim

The invention claimed is:

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.

Assignees

• Cambridge Entpr Ltd

Inventors

• Lachmann Peter

Classifications

• A61K38/16

  Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof {(enzyme inhibitors A61K38/005)} · CPC title

• A61K38/48

  acting on peptide bonds (3.4) · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K38/17

  from animals; from humans {(enzyme inhibitors A61K38/005)} · CPC title

• C12N9/48

  acting on peptide bonds (3.4) · CPC title