THERAPEUTIC USE OF ANTI-CD22 ANTIBODIES FOR INDUCING TROGOCYTOSIS

• US 20140212425A1
• Filed: 04/02/2014
• Published: 07/31/2014
• Est. Priority Date: 12/05/2011
• Status: Abandoned Application

• Current Assignee: Immunomedics, Inc. (Gilead Sciences Inc.)
• Original Assignee: Immunomedics, Inc. (Gilead Sciences Inc.)
• Inventors: Chang, Chien-Hsing, Goldenberg, David M., Hansen, Hans J., Rossi, Edmund A.
• Application Number:
  US14/243,512
• Publication Number:
  US 20140212425A1
• Time in Patent Office: Days
• US Class Current: 424/136.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07K 14/56 IFN-alpha
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2833 against MHC-molecules, e.g. HLA-molecules
• CPC Class Codes: C07K 16/2851 against the lectin superfamily, e.g. CD23, CD72
• CPC Class Codes: C07K 16/2887 against CD20
• CPC Class Codes: C07K 16/3007 Carcino-embryonic Antigens
• CPC Class Codes: C07K 16/468 Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/54 F(ab')2
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• 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 2317/77 Internalization into the cell
• CPC Class Codes: C07K 2317/90 characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
• 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
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide

Abstract

Disclosed are methods and compositions of anti-B cell antibodies, preferably anti-CD22 antibodies, for diagnosis, prognosis and therapy of B-cell associated diseases, such as B-cell malignancies, autoimmune disease and immune dysfunction disease. Preferably, the antibodies induce trogocytosis of B-cell antigens, such as CD19, CD20, CD21, CD22, CD79b, CD44, CD62L, or β7-integrin. Trogocytosis may play a significant role in determining antibody efficacy, disease responsiveness and prognosis of therapeutic intervention and trogocytosis-dependent responses may be monitored by measuring the levels of trogocytosis of one or more B-cell surface antigens induced by the bispecific antibody.

Claims

1. A method of treating a B-cell associated disease, selected from the group consisting of B-cell malignancy, autoimmune disease and immune dysfunction disease, comprising administering to a subject with the disease an antibody that binds to B cells, wherein the antibody induces trogocytosis of one or more B-cell surface antigens.

2. The method of claim 1, wherein the antibody induces trogocytosis of one or more B-cell surface antigens when exposed to B cells in vitro in the presence of PBMCs or purified Fcγ

R-positive cells.

3. The method of claim 1, wherein the antibody induces trogocytosis of one or more B-cell surface antigens when exposed to circulating B cells in vivo.

4. The method of claim 1, wherein the antibody induces trogocytosis of one or more B-cell surface antigens selected from the group consisting of CD19, CD20, CD21, CD22, CD79b, CD44, CD62L and β

7-integrin.

5. The method of claim 1, wherein the antibody binds to a B-cell antigen selected from the group consisting of CD19, CD20, CD21, CD22, CD79b, CD44, CD62L, CD74, HLA-DR, β

7-integrin and BCR.

6. The method of claim 1, wherein the subject is a human subject.

7. The method of claim 1, wherein the antibody is a chimeric, humanized, or human antibody.

8. The method of claim 1, wherein the antibody induces trogocytosis of one or more B-cell antigens, without depleting circulating B cells by more than 50%, when the antibody is administered to a subject.

9. The method of claim 1, wherein the antibody is effective to kill malignant B cells, without depleting circulating normal B cells by more than 50%, when the antibody is administered to a subject with a B-cell leukemia or lymphoma.

10. The method of claim 1, wherein the B-cell malignancy is selected from the group consisting of B-cell leukemia, B-cell lymphoma, Hodgkin'"'"'s lymphoma, non-Hodgkin'"'"'s lymphoma, Burkitt lymphoma, mantle cell lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, multiple myeloma and Waldenstrom'"'"'s macroglobulinemia.

11. The method of claim 1, wherein the autoimmune disease is selected from the group consisting of acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, dermatomyositis, Sydenham'"'"'s chorea, myasthenia gravis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, polyglandular syndromes, bullous pemphigoid, diabetes mellitus, Henoch-Schonlein purpura, post-streptococcal nephritis, erythema nodosum, Takayasu'"'"'s arteritis, ANCA-associated vasculitides, Addison'"'"'s disease, rheumatoid arthritis, multiple sclerosis, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa, ankylosing spondylitis, Goodpasture'"'"'s syndrome, thromboangitis obliterans, Sjö

gren'"'"'s syndrome, primary biliary cirrhosis, Hashimoto'"'"'s thyroiditis, thyrotoxicosis, scleroderma, chronic active hepatitis, polymyositis/dermatomyositis, polychondritis, bullous pemphigoid, pemphigus vulgaris, Wegener'"'"'s granulomatosis, membranous nephropathy, amyotrophic lateral sclerosis, tabes dorsalis, giant cell arteritis/polymyalgia, pernicious anemia, rapidly progressive glomerulonephritis, psoriasis and fibrosing alveolitis.

12. The method of claim 1, wherein the autoimmune disease is SLE (systemic lupus erythematosus).

13. The method of claim 1, wherein the immune dysfunction disease is selected from the group consisting of graft-versus-host disease, organ transplant rejection, septicemia, sepsis and inflammation.

14. The method of claim 1, further comprising administering a therapeutic agent to the subject.

15. The method of claim 14, wherein the therapeutic agent is selected from the group consisting of a drug, prodrug, immunomodulator, cytokine, chemokine, pro-apoptotic agent, anti-angiogenic agent, tyrosine kinase inhibitor, Bruton kinase inhibitor, sphingosine inhibitor, enzyme, hormone, photoactive agent, siRNA and RNAi.

16. The method of claim 15, wherein the drug is selected from the group consisting of 5-fluorouracil, aplidin, azaribine, anastrozole, anthracyclines, bendamustine, bleomycin, bortezomib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celecoxib, chlorambucil, cisplatinum, Cox-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicine (2PDOX), pro-2PDOX, cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, estramustine, epipodophyllotoxin, estrogen receptor binding agents, etoposide (VP16), etoposide glucuronide, etoposide phosphate, floxuridine (FUdR), 3′

,5′

-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, farnesyl-protein transferase inhibitors, gemcitabine, hydroxyurea, idarubicin, ifosfamide, L-asparaginase, lenolidamide, leucovorin, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, navelbine, nitrosourea, plicomycin, procarbazine, paclitaxel, pentostatin, PSI-341, raloxifene, semustine, streptozocin, tamoxifen, temazolomide (an aqueous form of DTIC), transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vinorelbine, vinblastine, vincristine and vinca alkaloids.

17. The method of claim 15, wherein the tyrosine kinase inhibitor is selected from the group consisting of canertinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, leflunomide, nilotinib, pazopanib, semaxinib, sorafenib, sunitinib, sutent and vatalanib.

18. The method of claim 15, wherein the Bruton kinase inhibitor is selected from the group consisting of PCI-32765 (ibrutinib), PCI-45292, GDC-0834, LFM-A13 and RN486.

19. The method of claim 15, wherein the immunomodulator is selected from the group consisting of a cytokine, a stem cell growth factor, a lymphotoxin, a hematopoietic factor, a colony stimulating factor, erythropoietin, thrombopoietin, tumor necrosis factor-α

(TNF-α

), TNF-β

, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-α

, interferon-β

, interferon-λ

, interferon-γ

, “

S1 factor”

, human growth hormone, N-methionyl human growth hormone, bovine growth hormone, parathyroid hormone, thyroxine, insulin, proinsulin, relaxin, prorelaxin, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), hepatic growth factor, prostaglandin, fibroblast growth factor, prolactin, placental lactogen, OB protein, mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, integrin, NGF-β

, platelet-growth factor, TGF-α

, TGF-β

, insulin-like growth factor-I, insulin-like growth factor-II, M-CSF, interleukin-1 (IL-1), IL-1α

, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-21, IL-23, IL-25, LIF, kit-ligand (FLT-3), angiostatin, thrombospondin, endostatin, and lymphotoxin.

20. The method of claim 15, wherein the anti-angiogenic agent is selected from the group consisting of angiostatin, baculostatin, canstatin, maspin, anti-placenta growth factor (anti-P1GF), anti-VEGF, anti-Flk-1 antibody, anti-Flt-1 antibody, anti-Kras antibody, anti-cMET antibody, anti-MIF (macrophage migration-inhibitory factor) antibody, laminin peptide, fibronectin peptide, plasminogen activator inhibitor, tissue metalloproteinase inhibitor, an interleukin-12, IP-10, Gro-β

, thrombospondin, 2-methoxyoestradiol, proliferin-related protein, carboxiamidotriazole, CM101, Marimastat, pentosan polysulphate, angiopoietin-2, interferon-alpha, interferon-lambda, herbimycin A, PNU145156E, 16K prolactin fragment, Linomide, thalidomide, pentoxifylline, genistein, TNP-470, endostatin, paclitaxel, accutin, angiostatin, cidofovir, vincristine, bleomycin, AGM-1470, platelet factor 4 and minocycline.

21. The method of claim 1, wherein the antibody is a bispecific antibody.

22. The method of claim 21, wherein the bispecific antibody comprises an IgG antibody and one or more antigen-binding antibody fragments.

23. The method of claim 22, wherein the bispecific antibody comprises an IgG antibody and four antigen-binding antibody fragments.

24. The method of claim 21, wherein the bispecific antibody binds to two different B-cell antigens selected from the group consisting of CD19, CD20, CD21, CD22, CD79b, CD44, CD62L, CD74, HLA-DR, β

7-integrin and BCR.

25. The method of claim 21, wherein the bispecific antibody binds to an antigen selected from the group consisting of TNF-alpha, IL6 and CD3.

26. The method of claim 21, wherein the bispecific antibody is an anti-CD22×

anti-CD20, anti-CD22×

anti-CD19, anti-CD22×

anti-CD21, anti-CD22×

anti-CD79b, anti-CD22×

anti-CD44, anti-CD22×

anti-CD62L, anti-CD22×

anti-β

7-integrin, anti-CD22×

anti-BCR, anti-CD22×

anti-β

7-integrin, anti-CD22×

anti-CD74, anti-CD22×

anti-HLA-DR, anti-CD22×

anti-TNF-alpha, anti-CD22×

anti-IL6 or anti-CD22×

anti-CD3 antibody.

27. The method of claim 21, wherein the bispecific antibody is an anti-CD20×

anti-CD19, anti-CD20×

anti-CD21, anti-CD20×

anti-CD74, anti-CD20×

anti-HLA-DR, anti-CD20×

anti-TNF-alpha, anti-CD20×

anti-IL6, anti-CD20×

anti-CD3, anti-CD19×

anti-CD21, anti-CD19×

anti-CD74, anti-CD19×

anti-HLA-DR, anti-CD19×

anti-TNF-alpha, anti-CD19×

anti-IL6, anti-CD19×

anti-CD3 antibody, anti-CD74×

anti-HLA-DR, anti-CD74×

anti-TNF-alpha, anti-CD74×

anti-IL6, anti-CD74×

anti-CD3, anti-HLA-DR×

anti-TNF-alpha, anti-HLA-DR×

anti-IL6, anti-HLA-DR×

anti-CD3, anti-TNF-alpha×

anti-IL6, anti-TNF-alpha×

anti-CD3, or anti-IL6×

anti-CD3 bispecific antibody.

28. The method of claim 21, wherein the bispecific antibody is an anti-CD22×

anti-CD20 antibody.

29. The method of claim 21, wherein the bispecific antibody comprises an anti-CD20 antibody or antigen-binding fragment thereof, wherein the anti-CD20 antibody is rituximab or veltuzumab.

30. The method of claim 21, wherein the bispecific antibody comprises an anti-CD22 antibody or antigen-binding fragment thereof, wherein the anti-CD22 antibody is epratuzumab or RFB4.

31. The method of claim 22, wherein the IgG antibody and the antigen-binding antibody fragment are fusion proteins.

32. The method of claim 22, wherein the antibody fragment is selected from the group consisting of F(ab′

)₂, F(ab)₂, Fab′

, Fab, Fv, scFv and single domain antibody fragments.

33. The method of claim 21, wherein the IgG antibody and antibody fragments are selected from the group consisting of chimeric, humanized, and human antibodies and antibody fragments.

34. The method of claim 21, wherein the bispecific antibody induces trogocytosis of one or more B-cell antigens, without depleting circulating B cells by more than 50%, when the antibody is administered to a subject.

35. The method of claim 21, wherein the bispecific antibody is effective to kill malignant B cells, without depleting circulating normal B cells by more than 50%, when the bispecific antibody is administered to a subject with a B-cell leukemia or lymphoma.

36. The method of claim 21, wherein the bispecific antibody is a complex comprising:

a) a first antibody, wherein the C-terminal end of each light chain of the first antibody is conjugated to an anchor domain (AD) moiety from an A-kinase anchoring protein (AKAP); and

b) an antigen-binding fragment of a second antibody, conjugated to a dimerization and docking domain (DDD) moiety from human protein kinase A (PKA) regulatory subunit RIa, RIβ

, RIIα

or RIIβ

;

wherein two copies of the DDD moiety form a dimer that binds to the AD moiety to form the complex.

51. A pharmaceutical composition comprising a complex according to claim 1.

37. A complex comprising:

a) a first anti-B-cell antibody, wherein the C-terminal end of each light chain of the first antibody is conjugated to an anchor domain (AD) moiety from an A-kinase anchoring protein (AKAP); and

b) an antigen-binding fragment of a second anti-B-cell antibody, conjugated to a dimerization and docking domain (DDD) moiety from human protein kinase A (PKA) regulatory subunit RIα

, RIβ

, RIIα

or RIIβ

;

wherein two copies of the DDD moiety form a dimer that binds to the AD moiety to form the complex.

38. The complex of claim 37, wherein the first and second antibodies bind to B-cell antigens selected from the group consisting of CD19, CD20, CD21, CD22, CD79b, CD44, CD62L and β

7-integrin.

39. The complex of claim 37, wherein the first and second antibodies bind to B-cell antigens selected from the group consisting of CD20 and CD22.

40. The complex of claim 37, wherein the complex induces trogocytosis of one or more B-cell antigens when exposed to B cells in vitro in the presence of peripheral blood mononuclear cells (PBMCs) or purified Fcγ

R-positive cells.

41. The complex of claim 40, wherein the complex induces trogocytosis of one or more B-cell antigens selected from the group consisting of CD19, CD20, CD21, CD22, CD79b, CD44, CD62L and β

7-integrin.

42. The complex of claim 37, wherein the complex induces trogocytosis of one or more B-cell antigens in vivo when the complex is administered to a subject.

43. The complex of claim 42, wherein the complex induces trogocytosis of one or more B-cell antigens selected from the group consisting of CD19, CD20, CD21, CD22, CD79b, CD44, CD62L and β

7-integrin.

44. The complex of claim 39, wherein the antibody that binds to CD22 is selected from the group consisting of epratuzumab and RFB4.

45. The complex of claim 39, wherein the antibody that binds to CD20 is selected from the group consisting of veltuzumab and rituximab.

46. The complex of claim 37, wherein the antibodies are chimeric, humanized, or human antibodies.

47. The complex of claim 37, wherein the first antibody and the antigen-binding fragment of the second antibody are fusion proteins.

48. The complex of claim 42, wherein the complex induces trogocytosis of one or more B-cell antigens without depleting circulating B cells by more than 50% when administered to a subject.

49. The complex of claim 42, wherein the complex is effective to kill malignant B cells without depleting circulating normal B cells by more than 50% when administered to a subject with a B-cell leukemia or lymphoma.

50. The complex of claim 42, wherein trogocytosis of one or more B-cell antigens is effective to treat autoimmune disease or immune system dysfunction when administered to a subject with autoimmune disease or immune system dysfunction.