Methods and compositions for inhibiting CD32B expressing cells

• US 20090136485A1
• Filed: 05/30/2008
• Published: 05/28/2009
• Est. Priority Date: 05/30/2007
• Status: Active Grant

• Current Assignee: Xencor, Inc.
• Original Assignee: Xencor, Inc.
• Inventors: Lazar, Gregory Alan, Karki, Sher Bahadur, Desjarlais, John R., Chu, Seung Yup, Moore, Gregory L., Vostiar, Igor
• Granted Patent: US 8,063,187 B2
• Time in Patent Office: Days
• US Class Current: 424/130.100
• 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 at least one cell comprising contacting the cell with an immunoglobulin,

wherein said immunoglobulin binds Fcγ

RIIb with s Kd of less than about 100 nM, and

wherein said immunoglobulin coengages a target antigen on the cell'"'"'s surface and Fcγ

RIIb on the cell'"'"'s surface.

2. The method of claim 1, wherein the immunoglobulin is a bispecific antibody comprising a first Fv region and a second Fv region, wherein said first Fv region binds the target antigen, and said second Fv region binds Fcγ

RIIb with a Kd of less than about 100 nM.

3. The method of claim 1, wherein said immunoglobulin is an Fc fusion comprising an Fc region, wherein said Fc region binds Fcγ

RIIb with a Kd of less than about 100 nM.

4. The method of claim 1, wherein the cell is a cancer cell.

5. The method of claim 1, wherein the cell is an immune cell.

6. The method of claim 5, wherein the cell is selected from the group consisting of a B cell, a plasma cell, a dendritic cell, a macrophage, a neutrophil, a mast cell, a basophil, and a eosinophil.

7. The method of claim 6, wherein the cell is a B cell.

8. The method of claim 7, wherein the target antigen is selected from the group consisting of CD19, CD20, CD21 (CR2), CD22, CD23/Fcε

RII, Fcε

RIα

, Fcε

RIβ

, Fcε

RIγ

, CD24/BBA-1/HSA, CD27, CD35 (CR1), CD38, CD40, CD45RA, CD52/CAMPATH-1/HE5, CD72, CD79a (Igα

), CD79b (Igβ

), IgM (μ

), CD80, CD81, CD86, Leu13, HLA-DR, -DP, -DQ, CD138, CD317/HM1.24, CD11a, CD11b, CD11c, CD14, CD68, CD163, CD172a, CD200R, and CD206.

9. The method of claim 1, wherein the target antigen is an autoantigen.

10. The method of claim 9, wherein the target antigen is selected from the group consisting of double-stranded DNA, platelet antigens, myelin protein antigen, Sm antigens in snRNPs, islet cell antigen, Rheumatoid factor, and anticitrullinated protein. citrullinated proteins and peptides such as CCP-1, CCP-2 (cyclical citrullinated peptides), fibrinogen, fibrin, vimentin, fillaggrin, collagen I and II peptides, alpha-enolase, translation initiation factor 4G1, perinuclear factor, keratin, Sa (cytoskeletal protein vimentin), components of articular cartilage such as collagen II, IX, and XI, circulating serum proteins such as RFs (IgG, IgM), fibrinogen, plasminogen, ferritin, nuclear components such as RA33/hnRNP A2, Sm, eukaryotic translation elogation factor 1 alpha 1, stress proteins such as HSP-65, -70, -90, BiP, inflammatory/immune factors such as B7-H1, IL-1 alpha, and IL-8, enzymes such as calpastatin, alpha-enolase, aldolase-A, dipeptidyl peptidase, osteopontin, glucose-6-phosphate isomerase, receptors such as lipocortin 1, neutrophil nuclear proteins such as lactoferrin and 25-35 kD nuclear protein, granular proteins such as bactericidal permeability increasing protein (BPI), elastase, cathepsin G, myeloperoxidase, proteinase 3, platelet antigens, myelin protein antigen, islet cell antigen, rheumatoid factor, histones, ribosomal P proteins, cardiolipin, vimentin, nucleic acids such as dsDNA, ssDNA, and RNA, ribonuclear particles and proteins such as Sm antigens (including but not limited to SmD'"'"'s and SmB′

/B), U1RNP, A2/B1 hnRNP, Ro (SSA), and La (SSB) antigens.

11. The method of claim 1, wherein the target antigen is an allergen.

12. An immunoglobulin having affinity for an antigen comprising an Fc variant of a parent Fc polypeptide,

wherein said Fc variant has an enhanced binding affinity to Fcγ

RIIb relative to the parent FC polypeptide,

wherein said antigen is selected from an autoantigen or an allergen, and

wherein said Fc variant coengages a target antigen on the cell'"'"'s surface and an Fcγ

R on the cell'"'"'s surface.

13. The immunoglobulin of claim 12, wherein said Fc variant comprises at least one amino acid modification in the Fc region compared to the parent Fc polypeptide,

wherein said modification is selected from the group consisting of 234, 235, 236, 237, 239, 265, 266, 267, 268, 298, 325, 326, 327, 328, 329, 330, 331, and 332, wherein numbering is according to the EU index.

14. The immunoglobulin of claim 13, wherein said at least one amino acid modification is at least one amino acid substitution selected from the group consisting of 234F, 234G, 234I, 234K, 234N, 234P, 234Q, 234S, 234V, 234W, 234Y, 234D, 234E, 235A, 235E, 235H, 235I, 235N, 235P, 235Q, 235R, 235S, 235W, 235Y, 235D, 235F, 235T, 236D, 236F, 236H, 236I, 236K, 236L, 236M, 236P, 236Q, 236R, 236S, 236T, 236V, 236W, 236Y, 236A, 236E, 236N, 237A, 237E, 237H, 237K, 237L, 237P, 237Q, 237S, 237V, 237Y, 237D, 237N, 239D, 239E, 239N, 239Q, 265E, 266D, 266I, 266M, 267A, 267D, 267E, 267G, 268D, 268E, 268N, 268Q, 298D, 298E, 298L, 298M, 298Q, 325L, 326A, 326E, 326W, 326D, 327D, 327G, 327L, 327N, 327Q, 327E, 328E, 328F, 328Y, 328H, 328I, 328Q, 328W, 329E, 330D, 330H, 330K, 330S, 331S, and 332E, wherein numbering is according to the EU index.

15. The immunoglobulin of claim 12, wherein said immunoglobulin is an Fc fusion comprising the Fc variant covalently linked to an autoantigen or an allergen.

16. An immunoglobulin having affinity for an antigen comprising an Fc variant of a parent Fc polypeptide,

wherein said Fc variant comprises at least two amino acid modifications in the Fc region compared to the parent Fc polypeptide,

wherein said modification is selected from the group consisting of 234, 235, 236, 237, 239, 265, 266, 267, 268, 298, 325, 326, 327, 328, 329, 330, 331, and 332, wherein numbering is according to the EU index.

wherein said Fc variant has an enhanced binding affinity to Fcγ

RIIb relative to the parent Fc polypeptide,

wherein said antigen is selected from a protein expressed on a Fcγ

RIIb+ cell, and

wherein said Fc variant coengages the antigen on the cell'"'"'s surface and an Fcγ

RIIb on the cell'"'"'s surface.

17. The immunoglobulin of claim 16, wherein said at least two modifications are at least two amino acid substitutions selected from the group consisting of 234F, 234G, 234I, 234K, 234N, 234P, 234Q, 234S, 234V, 234W, 234Y, 234D, 234E, 235A, 235E, 235H, 235I, 235N, 235P, 235Q, 235R, 235S, 235W, 235Y, 235D, 235F, 235T, 236D, 236F, 236H, 236I, 236K, 236L, 236M, 236P, 236Q, 236R, 236S, 236T, 236V, 236W, 236Y, 236A, 236E, 236N, 237A, 237E, 237H, 237K, 237L, 237P, 237Q, 237S, 237V, 237Y, 237D, 237N, 239D, 239E, 239N, 239Q, 265E, 266D, 266I, 266M, 267A, 267D, 267E, 267G, 268D, 268E, 268N, 268Q, 298D, 298E, 298L, 298M, 298Q, 325L, 326A, 326E, 326W, 326D, 327D, 327G, 327L, 327N, 327Q, 327E, 328E, 328F, 328Y, 328H, 328I, 328Q, 328W, 329E, 330D, 330H, 330K, 330S, 331S, and 332E, wherein numbering is according to the EU index.

18. The immunoglobulin of claim 16, wherein the Fcγ

RIIb+ cell is selected from the group consisting of a plasma cell, a dendritic cell, a macrophage, a neutrophil, a mast cell, a basophil, and a eosinophil.

19. The method of claim 18, wherein the cell is a B cell.

20. The method of claim 19, wherein the antigen is selected from the group consisting of CD19, CD20, CD21 (CR2), CD22, CD23/Fcε

RII, Fcε

RIα

, Fcε

RIβ

, Fcε

RIγ

, CD24/BBA-1/HSA, CD27, CD35 (CR1), CD38, CD40, CD45RA, CD52/CAMPATH -1/HE5, CD72, CD79a (Igα

), CD79b (Igβ

), IgM (μ

), CD80, CD81, CD86, Leu13, HLA-DR, -DP, -DQ, CD138, CD317/HM1.24, CD11a, CD11b, CD11c, CD14, CD68, CD163, CD172a, CD200R, and CD206.