Methods and compositions for inhibiting CD32B expressing cells

• US 9,394,366 B2
• Filed: 11/29/2012
• Issued: 07/19/2016
• Est. Priority Date: 05/30/2007
• Status: Active Grant

• Current Assignee: Xencor, Inc.
• Original Assignee: Xencor, Inc.
• Inventors: Chu, Seung Yup, Desjarlais, John R., Karki, Sher Bahadur, Lazar, Gregory Alan, Moore, Gregory L., Vostiar, Igor
• Primary Examiner(s): DAHLE, CHUN WU
• Application Number:
  US13/689,528
• Publication Number:
  US 20130315910A1
• Time in Patent Office: 1,328 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/283 against Fc-receptors, e.g. CD16, CD32, CD64 CD23 C07K16/2851
• CPC Class Codes: C07K 16/2851 against the lectin superfamily, e.g. CD23, CD72
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/524 CH2 domain
• CPC Class Codes: C07K 2317/53 Hinge
• CPC Class Codes: C07K 2317/71 Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/72 Increased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/734 : Complement-dependent cytotoxicity [CDC]
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• 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

Abstract

The present invention relates to immunoglobulins that bind FcγRIIb+ cells and coengage the antigen on the cell'"'"'s surface and an FcγRIIb on the cell'"'"'s surface, methods for their generation, and methods for using the immunoglobulins.

Claims

1. A method of inhibiting BCR activation of at least one B cell comprising contacting the B cell with an anti-CD19 antibody comprising:

an Fc region that binds Fcγ

RIIb on the cell surface with enhanced affinity as compared to a parent antibody comprising the amino acid sequence of SEQ ID NO;

4;

a light chain comprising an amino acid sequence of SEQ ID NO;

7;

a heavy chain comprising an amino acid sequence of SEQ ID NO;

2; and

at least one amino acid substitution in the Fc region selected from;

L235Y, L235R, G236D, S267D, S267E, and L328F as compared to SEQ ID NO;

4, wherein the numbering is according to the EU index, as in Kabat.

2. The method of claim 1, wherein the amino acid substitution(s) in the Fc region are selected from L235D/S267E, L235Y/S267E, L235D/S267D, L235I/S267E, L235I/S267D, L235Y/S267D, G236D/S267E, G236D/S267D, S267E/L328F, S267D/L328F, H268D/S267E, H268D/S267D, H268E/S267E, H268E/S267D, G236D/S267E/L328F, and G236N/S267E/L328F.

3. The method of claim 1, wherein the amino acid substitution(s) in the Fc region are selected from L235D/S267E, L235Y/S267E, L235Y/S267D, G236D/S267E, S267E/L328F, H268D/S267E, H268E/S267E, H268E/S267D, G236D/S267E/L328F, and G236D/S267E/L328F.

4. The method of claim 1, wherein the amino acid substitution in the Fc region is S267E.

5. The method of claim 1, wherein the amino acid substitution in the Fc region is L328F.

6. The method of claim 1, wherein the antibody comprises Fc substitutions S267E/L328F.

7. The method of claim 1, wherein the amino acid substitution(s) in the Fc region are selected from L235D/S267E, L235Y/S267E, L235Y/S267D, G236D/S267E, S267E/L328F, H268D/S267E, H268E/S267E, H268E/S267D, G236D/S267E/L328F, and G236D/S267E/L328F.

8. A method of treating an indication selected from systemic Sjogren'"'"'s syndrome, multiple sclerosis, lupus erythematosus (SLE), discoid lupus, and lupus erythematosis, in a patient in need of such treatment, comprising administering to said patient an anti-CD19 antibody comprising:

an Fc region that binds Fcγ

RIIb on the cell surface with enhanced affinity as compared to a parent antibody comprising the amino acid sequence of SEQ ID NO;

4;

a light chain comprising an amino acid sequence of SEQ ID NO;

7;

a heavy chain comprising an amino acid sequence of SEQ ID NO;

2; and

at least one amino acid substitution in the Fc region selected from

L235Y, L235R, G236D, S267D, S267E, and L328F

as compared to SEQ ID NO;

4, wherein the numbering is according to the EU index, as in Kabat.

9. The method of claim 8, wherein the amino acid substitution(s) in the Fc region are selected from L235D/S267E, L235Y/S267E, L235D/S267D, L235I/S267E, L235I/S267D, L235Y/S267D, G236D/S267E, G236D/S267D, S267E/L328F, S267D/L328F, H268D/S267E, H268D/S267D, H268E/S267E, H268E/S267D, G236D/S267E/L328F, and G236N/S267E/L328F.

10. The method of claim 8, wherein the indication is selected from discoid lupus, lupus erythematosis, and systemic lupus erythematosus.

11. The method of claim 8, wherein said antibody has reduced binding affinity for Fcγ

RIIIa as compared to a parent antibody.

12. The method of claim 8, wherein the antibody comprises Fc substitution S267E.

13. The method of claim 8, wherein the antibody comprises Fc substitution L328F.

14. The method of claim 8, wherein the antibody comprises Fc substitutions S267E and L328F.

15. A method of treating an indication selected from systemic Sjogren'"'"'s syndrome, multiple sclerosis, lupus erythematosus (SLE), discoid lupus, and lupus erythematosis, in a patient in need of such treatment, comprising administering to said patient an anti-CD19 antibody comprising:

an Fc region that binds Fcγ

RIIb on the cell surface with enhanced affinity as compared to a parent antibody comprising the amino acid sequence of SEQ ID NO;

4;

a light chain comprising an amino acid sequence of SEQ ID NO;

7; and

a heavy chain comprising an amino acid sequence of SEQ ID NO;

2 and amino acid substitution(s) in the Fc region selected from

L235Y, L235R, G236D, S267D, S267E, and L328F

as compared to SEQ ID NO;

4, wherein the numbering is according to the EU index, as in Kabat;

wherein the antibody inhibits said at least one B cell to treat the indication.

16. The method of claim 15, wherein the amino acid substitution(s) in the Fc region are selected from L235D/S267E, L235Y/S267E, L235D/S267D, L235I/S267E, L235I/S267D, L235Y/S267D, G236D/S267E, G236D/S267D, S267E/L328F, S267D/L328F, H268D/S267E, H268D/S267D, H268E/S267E, H268E/S267D, G236D/S267E/L328F, and G236N/S267E/L328F.

17. The method of claim 15, wherein the indication is selected from discoid lupus, lupus erythematosis, and systemic lupus erythematosus.

18. The method of claim 15, wherein said antibody has reduced binding affinity for Fcγ

RIIIa as compared to a parent antibody.

19. The method of claim 15, wherein the antibody comprises Fc substitution S267E.

20. The method of claim 15, wherein the antibody comprises Fc substitution L328F.

21. The method of claim 15, wherein the antibody comprises Fc substitutions S267E and L328F.

22. The method of claim 15, wherein the indication is selected from discoid lupus, lupus erythematosis, and systemic lupus erythematosus.