Optimized antibodies that target CD19

• US 8,524,867 B2
• Filed: 08/14/2007
• Issued: 09/03/2013
• Est. Priority Date: 08/14/2006
• Status: Active Grant

• Current Assignee: Xencor, Inc.
• Original Assignee: Xencor, Inc.
• Inventors: Bernett, Matthew J., Chu, Seung Yup, Desjarlais, John R., Karki, Sher Bahadur, Lazar, Gregory Alan, Pong, Erik WeiKing, Richards, John O., Zhukovsky, Eugene Alexander
• Primary Examiner(s): DAHLE, CHUN WU
• Application Number:
  US12/377,251
• Publication Number:
  US 20100272723A1
• Time in Patent Office: 2,212 Days
• Field of Search: None
• US Class Current: 530/387.1
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/41 Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/72 Increased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/732 Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/77 : Internalization into the cell
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

Antibodies that target CD19, wherein the antibodies comprise at least one modification relative to a parent antibody, wherein the modification alters affinity to an FcyR or alters effector function as compared to the parent antibody, and methods of using the antibodies.

Claims

1. An antibody that binds CD19, said antibody comprising a heavy chain and a light chain, said heavy chain comprising a variable region having a CDR1 comprising SEQ ID NO:

132, a CDR2 comprising SEQ ID NO;

147, and a CDR3 comprising SEQ ID NO;

116; and

said light chain comprising a variable region having a CDR1 comprising SEQ ID NO;

120, a CDR2comprising SEQ ID NO;

129, and a CDR3 comprising SEQ ID NO;

130, wherein the heavy chain comprises an Fc domain comprising an amino acid substitution at position S239 and/or 1332, wherein the numbering is according to the EU index as in Kabat.

2. The antibody according to claim 1, wherein said heavy chain variable region comprises SEQ ID NO:

40.

3. The antibody according to claim 1, wherein said light chain variable region comprises SEQ ID NO:

58.

4. An antibody according to claim 1, wherein said heavy chain comprises SEQ ID NO:

40 and said light chain sequence comprises SEQ ID NO;

58.

5. An antibody according to claim 1, wherein the amino acid substitution is at position S239, wherein the numbering is according to the EU index as in Kabat.

6. An antibody according to claim 2, wherein the amino acid substitution is at position S239, wherein the numbering is according to the EU index as in Kabat.

7. An antibody according to claim 3, wherein the amino acid substitution is at position S239, wherein the numbering is according to the EU index as in Kabat.

8. An antibody according to claim 4, wherein the amino acid substitution is at position S239, wherein the numbering is according to the EU index as in Kabat.

9. An antibody according to claim 5, wherein the substitution is S239D.

10. An antibody according to claim 6, wherein the substitution is S239D.

11. An antibody according to claim 7, wherein the substitution is S239D.

12. An antibody according to claim 8, wherein the substitution is S239D.

13. An antibody according to claim 1, wherein the amino acid substitution is at position l332, wherein the numbering is according to the EU index as in Kabat.

14. An antibody according to claim 2, wherein the amino acid substitution is at position l332, wherein the numbering is according to the EU index as in Kabat.

15. An antibody according to claim 3, wherein the amino acid substitution is at position l332, wherein the numbering is according to the EU index as in Kabat.

16. An antibody according to claim 4, wherein the amino acid substitution is at position l332, wherein the numbering is according to the EU index as in Kabat.

17. An antibody according to claim 13, wherein the substitution is l332E.

18. An antibody according to claim 14, wherein the substitution is l332E.

19. An antibody according to claim 15, wherein the substitution is l332E.

20. An antibody according to claim 16, wherein the substitution is l332E.

21. An antibody according to claim 1, further comprising an Fc domain having amino acid substitutions S239D and l332E, wherein the numbering is according to the EU index as in Kabat.

22. An antibody according to claim 2, further comprising an Fc domain comprising amino acid substitutions S239D and l332E, wherein the numbering is according to the EU index as in Kabat.

23. An antibody according to claim 3, further comprising an Fc domain comprising amino acid substitutions S239D and l332E, wherein the numbering is according to the EU index as in Kabat.

24. An antibody according to claim 4, further comprising an Fc domain comprising amino acid substitutions S239D and l332E, wherein the numbering is according to the EU index as in Kabat.

25. A composition comprising a plurality of glycosylated antibodies according to claim 1, wherein about 80-100% of the glycosylated antibody in the composition comprises a mature core carbohydrate structure which lacks fucose.

26. A composition comprising a plurality of glycosylated antibodies according to claim 2, wherein about 80-100% of the glycosylated antibody in the composition comprises a mature core carbohydrate structure which lacks fucose.

27. A composition comprising a plurality of glycosylated antibodies according to claim 3, wherein about 80-100% of the glycosylated antibody in the composition comprises a mature core carbohydrate structure which lacks fucose.

28. A composition comprising a plurality of glycosylated antibodies according to claim 4, wherein about 80-100% of the glycosylated antibody in the composition comprises a mature core carbohydrate structure which lacks fucose.

29. A pharmaceutical composition comprising an antibody according claim 1 and a pharmaceutically acceptable carrier.

30. A pharmaceutical composition comprising an antibody according claim 2 and a pharmaceutically acceptable carrier.

31. A pharmaceutical composition comprising an antibody according claim 3 and a pharmaceutically acceptable carrier.

32. A pharmaceutical composition comprising an antibody according claim 4 and a pharmaceutically acceptable carrier.