Optimized antibodies that target CD19

• US 9,803,020 B2
• Filed: 08/05/2013
• Issued: 10/31/2017
• 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:
  US13/959,587
• Publication Number:
  US 20140086906A1
• Time in Patent Office: 1,548 Days
• Field of Search: None
• 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

The present invention describes antibodies that target CD19, wherein the antibodies comprise at least one modification relative to a parent antibody, wherein the modification alters affinity to an FcgγR or alters effector function as compared to the parent antibody. Also disclosed are methods of using the antibodies of the invention.

Claims

1. A method of treating a disease or disorder selected from the group consisting of non-Hodgkin'"'"'s lymphomas (NHL), chronic lymphocytic leukemia (CLL), B-cell acute lymphoblastic leukemia/lymphoma (B-ALL), and mantle cell lymphoma (MCL), wherein said method comprises administering 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 CDR2 comprising 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 I332, wherein the Fc numbering is according to the EU index as in Kabat.

2. The method of treating a disease or disorder according to claim 1, wherein the disease or disorder is non-Hodgkin'"'"'s lymphomas (NHL).

3. The method of treating a disease or disorder according to claim 1, wherein the disease or disorder is chronic lymphocytic leukemia (CLL).

4. The method of treating a disease or disorder according to claim 1, wherein the disease or disorder is B-cell acute lymphoblastic leukemia/lymphoma (B-ALL).

5. The method of treating a disease or disorder according to claim 1, wherein the disease or disorder is mantle cell lymphoma (MCL).

6. The method of treating a disease or disorder according to claim 1, wherein said heavy chain variable region comprises SEQ ID NO:

40.

7. The method of treating a disease or disorder according to claim 1, wherein said light chain variable region comprises SEQ ID NO:

58.

8. The method of treating a disease or disorder according to claim 1, wherein said heavy chain comprises SEQ ID NO:

40 and said light chain sequence comprises SEQ ID NO;

58.

9. The method of treating a disease or disorder according to claim 1, wherein the amino acid substitution is at position S239.

10. The method of treating a disease or disorder according to claim 6, wherein the amino acid substitution is at position S239.

11. The method of treating a disease or disorder according to claim 7, wherein the amino acid substitution is at position S239.

12. The method of treating a disease or disorder according to claim 8, wherein the amino acid substitution is at position S239.

13. The method of treating a disease or disorder according to claim 1, wherein the amino acid substitution is at position I332.

14. The method of treating a disease or disorder according to claim 6, wherein the acid substitution is at position I332.

15. The method of treating a disease or disorder according to claim 7, wherein the amino acid substitution is amino acid substitution at position I332.

16. The method of treating a disease or disorder according to claim 8, wherein the amino acid substitution is at position I332.

17. The method of treating a disease or disorder according to claim 1, wherein the amino acid substitutions are S239D and I332E.

18. The method of treating a disease or disorder according to claim 6, wherein the amino acid substitutions are S239D and I332E.

19. The method of treating a disease or disorder according to claim 7, wherein the amino acid substitutions are S239D and I332E.

20. The method of treating a disease or disorder according to claim 8, wherein the amino acid substitutions are S239D and I332E.

21. The method of treating a disease or disorder according to claim 1, wherein said method comprises administering a composition comprising a plurality of glycosylated antibodies that bind 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 CDR2 comprising SEQ ID NO;

129, and a CDR3 comprising SEQ ID NO;

130, wherein about 80-100% of the glycosylated antibodies in the composition comprise a mature core carbohydrate structure which lacks fucose, and wherein the heavy chain comprises an Fc domain comprising an amino acid substitution at position S239 and/or I332, the Fc numbering is according to the EU index as in Kabat.

22. The method of treating a disease or disorder according to claim 1, wherein said heavy chain variable region comprises SEQ ID NO:

87.

23. The method of treating a disease or disorder according to claim 1, wherein said light chain variable region comprises SEQ ID NO:

106.

24. The method of treating a disease or disorder according to claim 1, wherein said heavy chain variable region comprises SEQ ID NO:

87 and said light chain variable region comprises SEQ ID NO;

106.