Humanized anti-factor D antibodies and uses thereof

Patent metadata

Field	Value
Publication number	US-9676868-B2
Application number	US-201314033175-A
Country	US
Kind code	B2
Filing date	Sep 20, 2013
Priority date	Apr 28, 2008
Publication date	Jun 13, 2017
Grant date	Jun 13, 2017

Abstract

The invention relates to anti-Factor D antibodies, their nucleic acid and amino acid sequences, the cells and vectors that harbor these antibodies and 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. These antibodies are useful for diagnostics, prophylaxis and treatment of disease.

First claim

We claim:

1. A method for treating a complement-associated ocular disease, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-Factor D antibody or an antigen-binding fragment thereof, wherein the anti-Factor D antibody or antigen-binding fragment thereof comprises:
(a) a light chain variable domain comprising: (1) light chain HVR-1 (HVR-L1) comprising the sequence ITSTDIDDDMN (SEQ ID NO: 30) or a sequence that differs from SEQ ID NO: 30 by one or more amino acid substitutions, wherein said one or more substitutions are substitution of the amino acid residue at position 10 of SEQ ID NO: 30 to L or I and/or substitution of the amino acid at position 11 of SEQ ID NO: 30 to A or Q, (2) light chain HVR-2 (HVR-L2) comprising the sequence GGNTLRP (SEQ ID NO: 35) or a sequence that differs from SEQ ID NO: 35 by one amino acid substitution, wherein said one substitution is substitution of the amino acid residue at position 3 of SEQ ID NO: 35 to S or A, and, (3) light chain HVR-3 (HVR-L3) comprising the sequence LQSDSLPYT (SEQ ID NO: 38); and
(b) a heavy chain variable domain comprising: (1) heavy chain HVR-1 (HVR-H1) comprising the sequence GYTFTNYGMN (SEQ ID NO: 39), (2) heavy chain HVR-2 (HVR-H2) comprising the sequence WINTYTGETTYADDFKG (SEQ ID NO: 40), and (3) heavy chain HVR-3 (HVR-H3) comprising the sequence EGGVNN (SEQ ID NO: 41) or a sequence that differs from SEQ ID NO: 41 by one or more amino acid substitutions, wherein said one or more substitutions are substitution of the amino acid residue at position 5 of SEQ ID NO: 41 with A or Q and/or substitution of the amino acid residue at position 6 of SEQ ID NO: 41 with A or Q,
wherein said antibody or antigen-binding fragment thereof comprises at least one of the substitutions set forth in (a)(1), (a)(2), or (b)(3) above and/or the heavy chain variable domain comprises an E at position 1.

2. The method of claim 1 , wherein the anti-Factor D antibody or antigen-binding fragment thereof comprises an E at position 1 of the heavy chain variable domain.

3. The method of claim 2 , wherein the light chain variable domain comprises the amino acid sequence of DIQVTQSPSSLSASVGDRVTITCITSTDIDDDX 4 X 5 WYQQKPGKVPKLLISGGX 6 -TLRPGVP SRFSGSGSGTDFTLTISSLQPEDVATYYCLQSDSLPYTFGQGTKX 7 EIK (SEQ ID NO: 73), wherein X 4 is M, L or I; X 5 is N, A or Q; X 6 is N, S or A; and X 7 is L or V.

4. The method of claim 3 , wherein X 7 is V.

5. The method of claim 1 , wherein (a) the heavy chain variable domain comprises: i. an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 39; ii. an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 40; and iii. an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44 or SEQ ID NO: 45; and (b) the light chain variable domain comprises: iv. an HVR-L1 comprising the amino acid sequence selected from SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34; v. an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35, SEQ ID NO: 36 or SEQ ID NO: 37; and vi. an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 38.

6. The method of claim 5 , wherein the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 41.

7. The method of claim 5 , wherein the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 30.

8. The method of claim 5 , wherein the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 35.

9. The method of claim 5 , wherein the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 30, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 35, and the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 38.

10. The method of claim 5 , wherein the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 39, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 40, the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 41, the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 30, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 35, and the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 38.

11. The method of claim 10 , wherein the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 1, and wherein the amino acid residue at position 104 of SEQ ID NO: 1 is substituted with V.

12. The method of claim 11 , wherein the amino acid residue at position 1 of the heavy chain variable domain is an E.

13. The method of claim 1 , wherein the heavy chain variable domain comprises the sequence of SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO: 29.

14. The method of claim 1 , wherein the light chain variable domain comprises the sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, or SEQ ID NO: 14.

15. A method for treating a complement-associated ocular disease, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-Factor D antibody or an antigen-binding fragment thereof, wherein the anti-Factor D antibody or antigen-binding fragment thereof comprises a polypeptide comprising the following amino acid sequence: X 1 QLVQSGPELKKPGASVKVSCKASGYTFTNYGMNVVVRQAPGQGLEVVMGWINTYT G ETTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCEREGGVX 2 X 3 WGQGTLVTV S S (SEQ ID NO: 74), wherein X 1 is E; X 2 is N, A or Q; and X 3 is N, A or Q.

16. The method of claim 15 , wherein the anti-Factor D antibody or antigen-binding fragment thereof further comprises a polypeptide comprising the following amino acid sequence: DIQVTQSPSSLSASVGDRVTITCITSTDIDDDX 4 X 5 WYQQKPGKVPKLLISGG-X 6 TLRPGVP SRFSGSGSGTDFTLTISSLQPEDVATYYCLQSDSLPYTFGQGTKX 7 EIK (SEQ ID NO:73), wherein X 4 is M, L or I; X 5 is N, A or Q; X 6 is N, S or A; and X 7 is L or V.

17. A method for treating a complement-associated ocular disease, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-Factor D antibody or an antigen-binding fragment thereof, wherein the anti-Factor D antibody or antigen-binding fragment thereof comprises the heavy chain variable domain sequence of SEQ ID NO: 19.

18. The method of claim 17 , wherein the anti-Factor D antibody or antibody fragment thereof further comprises the light chain variable domain sequence of SEQ ID NO: 7.

19. A method for treating a complement-associated ocular disease, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-Factor D antibody or an antigen-binding fragment thereof, wherein the anti-Factor D antibody or antigen-binding fragment thereof comprises the heavy chain sequence of SEQ ID NO: 63.

20. The method of claim 19 , wherein the anti-Factor D antibody or antigen-binding fragment thereof further comprises the light chain sequence of SEQ ID NO: 61.

21. A method for treating a complement-associated ocular disease, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-Factor D antibody or an antigen-binding fragment thereof, wherein the anti-Factor D antibody or antigen-binding fragment thereof comprises: (a) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 1, wherein the amino acid residue at position 104 of SEQ ID NO: 1 is substituted with V; and (b) a heavy chain variable domain comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 39, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 40, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO:

Assignees

• Genentech Inc

Inventors

• Huang Arthur
• Kelley Robert
• Lowman Henry
• Van Lookeren Campagne Menno
• Winter Charles

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P27/00

  Drugs for disorders of the senses · CPC title