Anti-factor D antibody variant conjugates and uses thereof

Patent metadata

Field	Value
Publication number	US-10654932-B2
Application number	US-201615336522-A
Country	US
Kind code	B2
Filing date	Oct 27, 2016
Priority date	Oct 30, 2015
Publication date	May 19, 2020
Grant date	May 19, 2020

Abstract

The disclosure relates to antibody-polymer conjugates comprising one or more anti-Factor D antibody variants, their production and their use in the preparation of compositions and medicaments for treatment of diseases and disorders associated with excessive or uncontrolled complement activation.

First claim

We claim:

1. A conjugate comprising one or more anti-Factor D antibody covalently linked to one or more polyols, wherein at least one anti-Factor D antibody in the conjugate is an anti-Factor D antibody having a light chain having the amino acid sequence of SEQ ID NO: 28 and a heavy chain having the amino acid-sequence of SEQ ID NO: 32; and the polyol is a multi-armed polyol.

2. The conjugate according to claim 1 , wherein the polyol is covalently linked to at least one of the anti-Factor D antibodies at a free sulfhydryl group of a cysteine residue.

3. The conjugate of claim 2 , wherein the cysteine residue is an engineered cysteine.

4. The conjugate according to claim 2 , wherein the cysteine residue is in a constant domain of the anti-Factor D antibody.

5. The conjugate according to claim 2 , wherein the cysteine residue is at the C′-terminal end of the anti-Factor D antibody.

6. The conjugate according to claim 2 , wherein the conjugate comprises at least two anti-Factor D antibodies, and the polyol is covalently linked to each anti-Factor D antibody at a free sulfhydryl group of a cysteine residue.

7. The conjugate according to claim 1 , wherein the polyol is covalently linked to at least one of the anti-Factor D antibodies at a free amino group of a lysine residue.

8. The conjugate according to claim 7 , wherein the lysine residue is within a constant domain of the anti-Factor D antibody.

9. The conjugate according to claim 1 , wherein at least two anti-Factor D antibodies are covalently linked to the polyol.

10. The conjugate according to claim 1 , wherein the multi-armed polyol is selected from the group consisting of a dimer, a tetramer, a hexamer, and an octamer.

11. The conjugate according to claim 10 , wherein the multi-armed polyol is an octamer.

12. The conjugate according to claim 1 , wherein the polyol is polyethylene glycol.

13. The conjugate according to claim 12 , wherein the polyethylene glycol has a weight average molecular weight of from about 500 D to about 300,000 D.

14. The conjugate according to claim 13 , wherein the polyethylene glycol has a weight average molecular weight of from about 20,000 D to about 60,000 D.

15. The conjugate according to claim 14 , wherein the polyethylene glycol has a weight average molecular weight of about 40,000 D.

16. The conjugate according to claim 12 , wherein the polyethylene glycol has the structure of general formula (Ia):

wherein each m is independently an integer from 3-250; n is an integer from 1-10; each R 1 is independently either absent, or is a linking group; and each R 2 is independently either hydrogen or a terminal reactive group; wherein at least one R 2 is a terminal reactive group and is covalently linked to the anti-Factor D antibody.

17. The conjugate according to claim 12 , wherein the polyethylene glycol has the structure of general formula (Ib):

wherein each m is independently an integer from 3-250; each R 1 is independently either absent, or is a linking group; and each R 2 is independently either hydrogen or a terminal reactive group; wherein at least one R 2 is a terminal reactive group and is covalently linked to the anti-Factor D antibody.

18. The conjugate according to claim 12 , wherein the polyethylene glycol has the structure of general formula (IIa):

wherein each m is independently an integer of from 3-250; n is an integer from 1-10;
each R 1 is independently either absent, or is a linking group; and each R 2 is independently either hydrogen or a terminal reactive group; wherein at least one R 2 is a terminal reactive group and is covalently linked to the anti-Factor D antibody.

19. The conjugate according to claim 18 , wherein n is 6.

20. The conjugate according to claim 12 , wherein the polyethylene glycol has the structure of general formula (IIIa):

wherein each m is independently an integer of from 3-250; n is an integer from 1-10; each R 1 is independently either absent, or is a linking group; and each R 2 is independently either hydrogen or a terminal reactive group; wherein at least one R 2 is a terminal reactive group and is covalently linked to the anti-Factor D antibody.

21. The conjugate according to claim 20 , wherein n is 4.

22. The conjugate according to claim 12 , wherein the polyethylene glycol has the structure of general formula (IVa):

wherein each m is independently an integer of from 3-250; each R 1 is independently either absent, or is a linking group; and each R 2 is independently either hydrogen or a terminal reactive group; wherein at least one R 2 is a terminal reactive group and is covalently linked to the anti-Factor D antibody.

23. The conjugate according to claim 17 , wherein m is an integer of 50-200.

24. The conjugate according to claim 23 , wherein m is an integer of 100-150.

25. The conjugate according to claim 17 , wherein at least one R 1 is a linking group, wherein R 1 and R 2 when taken together are selected from the group consisting of

and combinations thereof; wherein each i is independently an integer of 0-10; and j is an integer of 0-10.

26. The conjugate according to claim 17 , wherein each R 2 is independently selected from the group consisting of a thiol reactive group, an amino reactive group, and combinations thereof.

27. The conjugate according to claim 26 , wherein each R 2 is independently selected from the group consisting of a maleimide, a sulfhydryl, a thiol, trifluoromethanesulfonate, tosylate, aziridine, epoxide, a pyridyl disulfide, succinimidyl ester, —NH 2 , an aldehyde, a haloacetate, a haloacetamide, and a para-nitrophenyl carbonate.

28. The conjugate according to claim 17 , wherein R 2 is a maleimide.

29. The conjugate according to claim 17 , wherein R 1 and R 2 , when taken together, are

i is an integer of 0-10; and j is an integer of 0-10.

30. The conjugate according to claim 17 , wherein at least seven of the R 2 groups are covalently linked to one of the anti-Factor D antibodies.

31. The conjugate according to claim 30 , wherein eight of the R 2 groups are covalently linked to one of the anti-Factor D antibodies.

32. A conjugate comprising at least one anti-Factor D antibody covalently linked to a polyethylene glycol, wherein the polyethylene glycol has the structure of general formula (Ib):

wherein each m is independently an integer from 3-250; each R 1 is independently either absent, or is a linking group; and each R 2 is ind

Assignees

• Genentech Inc

Inventors

• Hass Philip E
• Kelley Robert F
• Scheer Justin M
• Shatz Whitney
• Tesar Devin
• Van Lookeren Campagne Menno

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61K47/60 Primary

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07K16/22

  against growth factors {; against growth regulators} · CPC title

• A61K2039/505

  comprising antibodies · CPC title