Immunotherapy of B cell malignancies and autoimmune diseases using unconjugated antibodies and conjugated antibodies and antibody combinations and fusion proteins

• US 7,534,427 B2
• Filed: 12/30/2003
• Issued: 05/19/2009
• Est. Priority Date: 12/31/2002
• Status: Active Grant

• Current Assignee: Immunomedics, Inc.
• Original Assignee: Immunomedics, Inc.
• Inventors: Goldenberg, David M., Hansen, Hans J.
• Primary Examiner(s): HUYNH, PHUONG N
• Application Number:
  US10/747,199
• Publication Number:
  US 20040219156A1
• Time in Patent Office: 1,967 Days
• Field of Search: None
• US Class Current: 424/130.1
• CPC Class Codes: A61K 51/1018 against material from animals or humans
• CPC Class Codes: A61K 51/1045 against animal or human tumor cells or tumor cell determinants
• CPC Class Codes: A61K 51/109 immunoglobulins having two or more different antigen-binding sites or multifunctional antibodies
• CPC Class Codes: A61K 51/1093 conjugates with carriers being antibodies
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• 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 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 16/2812 : against CD4
• CPC Class Codes: C07K 16/2815 : against CD8
• CPC Class Codes: C07K 16/2821 : against ICAM molecules, e.g. CD50, CD54, CD102
• CPC Class Codes: C07K 16/2827 : against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 16/2845 : against integrin beta2-subunit-containing molecules, e.g. CD11, CD18
• 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 16/2887 : against CD20
• CPC Class Codes: C07K 16/2893 : against CD52
• CPC Class Codes: C07K 16/2896 : against molecules with a "CD"-designation, not provided for elsewhere

Abstract

The invention is directed to a method for treating a treating and diagnosing a B cell-related disease, T cell-related disease or an autoimmune disease in a mammal by concurrently or sequentially administering to the mammal a therapeutic composition that comprises a pharmaceutically acceptable vehicle and at least one conjugated antibody, wherein predosing with a non-radiolabeled antibody is not performed.

Claims

1. A method for treating a B-cell-related malignancy disease in a human comprising administering to said human either

(i) a conjugated anti-CD74 antibody or an antigen-binding fragment thereof

and

an unconjugated anti-CD20 antibody or an antigen-binding fragment thereof,

wherein said conjugated anti-CD74 antibody or antigen-binding fragment thereof and said unconjugated anti-CD20 antibody or antigen-binding fragment thereof are administered concurrently or sequentially

or

(ii) a conjugated anti-CD20 antibody or an antigen-binding fragment thereof

and

an unconjugated anti-CD74 antibody, or an antigen-binding fragment thereof,

wherein said conjugated anti-CD20 antibody or antigen-binding fragment thereof and said unconjugated anti-CD74 antibody or antigen-binding fragment thereof are administered concurrently or sequentially,

wherein predosing with a non-radiolabeled antibody is not performed and wherein the unconjugated anti-CD20 or unconjugated anti-CD74 is added as a maintenance therapy to keep proliferating tumor cells from target escape.

2. The method of claim 1, wherein the conjugated anti-CD20 antibody or antigen-binding fragment thereof is a humanized A20 (hA20) antibody or antigen-binding fragment thereof.

3. The method of claim 1, wherein

in (i), said unconjugated anti-CD20 antibody or antigen-binding fragment thereof is administered simultaneously with said conjugated anti-CD74 antibody or antigen-binding fragment thereof, and

in (ii), said unconjugated anti-CD74 antibody or antigen-binding fragment thereof is administered simultaneously with said conjugated anti-CD20 antibody or antigen-binding fragment thereof.

5. The method of claim 1, wherein, in either (i) or (ii), said unconjugated antibody or antigen-binding fragment thereof is administered after said conjugated antibody or antigen-binding fragment thereof.

6. The method of claim 1, wherein said conjugated and unconjugated antibody or antigen-binding fragment thereof is a human or humanized antibody or antigen-binding fragment thereof.

7. The method of claim 1, wherein said conjugated antibody or antigen-binding fragment thereof is conjugated to a therapeutic agent selected from the group consisting of a drug, a toxin, an immunomodulator, a chelator, a boron compound, a photoactive agent, and a radionuclide.

8. The method of claim 1, wherein the B-cell-related malignancy disease is a B-cell lymphoma, B-cell acute lymphocytic leukemia, B-cell chronic lymphocytic leukemia, or multiple myeloma.

9. The method of claim 1, wherein said conjugated antigen-binding fragment thereof is conjugated to 90Y-DOTA.

10. The method of claim 1, wherein the B-cell-related malignancy disease is non-Hodgkin'"'"'s lymphoma (NHL).

11. The method of claim 1, wherein the antigen-binding fragment is selected from the group consisting of F(ab)₂, Fab, Fv, sFv, scFv and diabody.

12. The method of claim 7, wherein said conjugated antibody or antigen-binding fragment thereof is conjugated to a drug selected from the group consisting of an antimitotic agent, an alkylating agent, an antimetabolite agent, an antiangiogenic agent, an apoptotic agent, an alkaloid agent, and antibiotic and a combination thereof.

13. The method of claim 7, wherein said conjugated antibody or antigen-binding fragment thereof is conjugated to a drug selected from the group consisting of a nitrogen mustard, an ethylenimine, an alkyl sulfonate, a nitrosourea, a triazene, a folic acid analog, an anthracycline, a taxane, a COX-2 inhibitor, a pyrimidine analog, a purine analog, an antibiotic, an enzyme, an epipodophyllotoxin, a platinum coordination complex, a vinca alkaloid, a substituted urea, a methyl hydrazine derivative, an adrenocortical suppressant, an endostatin, a taxol, a camptothecin, a doxorubicin, and a combination thereof.

14. The method of claim 7, wherein said conjugated antibody or antigen-binding fragment thereof is conjugated to a drug selected from the group consisting of cyclophosphamide, etoposide, vincristine, procarbazine, prednisone, carmustine, doxorubicin, methotrexate, bleomycin, dexamethasone, phenyl butyrate, bryostatin-1, and leucovorin.

15. The method of claim 7, wherein said conjugated antibody or antigen-binding fragment thereof is conjugated to a toxin selected from the group consisting of ricin, abrin, alpha toxin, saporin, ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtherin toxin, Pseudomonas exotoxin, and Pseudomonas endotoxin.

16. The method of claim 7, wherein said conjugated antibody or antigen-binding fragment thereof is conjugated to an immunomodulator selected from the group consisting of a cytokine, a stem cell growth factor, a lymphotoxin, a hematopoietic growth factor, a colony stimulating factor (CSF), an interferon (IFN), erythropoietin, thrombopoietin and a combination thereof.

17. The method of claim 7, wherein said conjugated antibody or antigen-binding fragment thereof is conjugated to an immunomodulator selected from the group consisting of IL-I, IL-2, IL-3, IL-6, IL-10, IL-12, IL-18, G-CSF, GM-CSF, interferon-α

, -β

or γ

, TNF-α and

stem cell growth factor.

18. The method of claim 7, wherein said radionuclide is bound to said chelator selected from the group consisting of DTPA, DOTA, TETA and NOTA.

19. The method of claim 7, wherein said therapeutic agent is selected from the group consisting of tumor necrosis factor, hematopoietic growth factor, colony stimulating factor, interferon, and stem cell growth factor.

20. The method of claim 18, wherein said radionuclide decays by beta particle emission and is selected from the group consisting of P-32, P-33, Sc-47, Fe-59, Cu-64, Cu-67, Se-75, As-77, Sr-89, Y-90, Mo-9, Rh-105, Pd-109, Ag-111, I-125, I-131, Pr-142, Pr-143, Pm-149, Sm-153, Tb-161, Ho-166, Er-169, Lu-177, Re-186, Re-188, Re-189, Ir-194, Au-198, Au-199, Pb-211, Pb-212, and Bi-213.

21. The method of claim 20, wherein said radionuclide has a maximum decay energy of 20-5,000 keV.

22. The method of claim 20, wherein said radionuclide has a maximum decay energy of 100-4,000 keV.

23. The method of claim 20, wherein said radionuclide has a maximum decay energy of 500-2,500 keV.

24. The method of claim 18, wherein said radionuclide decays by Auger particle emission and is selected from the group consisting of Co-58, Ga-67, Br-80rn, Tc-99m, Rh-103m, Pt-109, In-111, Sb-119, I-125, Ho-161, Os-189m and Ir-192.

25. The method of claim 24, wherein said radionuclide has a maximum decay energy of less than 1,000 keV.

26. The method of claim 24, wherein said radionuclide has a maximum decay energy of less than 100 keV.

27. The method of claim 24, wherein said radionuclide has a maximum decay energy of less than 70 keV.

28. The method of claim 18, wherein said radionuclide decays by alpha-particle emission and is selected from the group consisting of Ac-225, Dy-152, At-211, Bi-212, Ra-223, Rn-219, Po-215, Bi-211, Fr-221, At-217, Bi-213 and Fm-255.

29. The method of claim 28, wherein said radionuclide has a maximum decay energy of 2,000-9,000 keV.

30. The method of claim 28, wherein said radionuclide has a maximum decay energy of 3,000-8,000 keV.

31. The method of claim 28, wherein said radionuclide has a maximum decay energy of 4,000-7,000 keV.

32. The method of claim 7, wherein said therapeutic agent is used in photodynamic therapy or neutron capture procedures.

33. The method of claim 32, wherein said photodynamic therapy uses metal complexes, and said metal complexes are selected from the group consisting of zinc, aluminum, gallium, lutetium and palladium.

34. The method of claim 32, wherein said neutron capture procedures uses a radionuclide selected from the group consisting of B-10, Gd-157 and U-235.

35. The method of claim 8, wherein said B-cell lymphoma is an indolent form of B-cell lymphoma or an aggressive form of B-cell lymphoma.

36. The method of claim 1, wherein a ratio of targeted anti-CD20 or anti-CD74 antigen on diseased tissue exceeds that on normal tissue by a ratio of more than 1.6:

1.

37. The method of claim 1, wherein a ratio of targeted anti-CD20 or anti-CD74 antigen on diseased tissue exceeds that on normal tissue by a ratio of 5:

1.

40. The method of claim 1, wherein said B-cell-related malignancy disease is multiple myeloma.

41. A method for treating a B-cell-related malignancy disease in a human as claimed in claim 1, comprising administering to said human either

(a) a combination consisting of

(i) a conjugated anti-CD74 antibody or antigen-binding fragment thereof

and

(ii) an unconjugated anti-CD20 antibody or antigen-binding fragment thereof,

and

(iii) at least one member selected from the group consisting of a pharmaceutically acceptable vehicle, an immunomodulator, and a chemotherapeutic drug

wherein said conjugated anti-CD74 antibody or antigen-binding fragment thereof and said unconjugated anti-CD20 antibody or antigen-binding fragment thereof are administered concurrently or sequentially;

or

(b) a combination consisting of

(i) a conjugated anti-CD20 antibody or antigen-binding fragment thereof

and

(ii) an unconjugated anti-CD74 antibody or antigen-binding fragment thereof,

and

(iii) at least one member selected from the group consisting of a pharmaceutically acceptable vehicle, an immunomodulator, and a chemotherapeutic drug

wherein said conjugated anti-CD20 antibody or antigen-binding fragment thereof and said unconjugated anti-CD74 antibody or antigen-binding fragment thereof are administered concurrently or sequentially,

and wherein predosing with a non-radiolabeled antibody is not performed and wherein the unconjugated anti-CD20 or unconjugated anti-CD74is added as a maintenance therapy to keep proliferating tumor cells from target escape.

4. A method for treating a B-cell related malignancy disease in a human comprising administering to said human a bispecific antibody that binds to both CD74 and CD20, said bispecific antibody comprising either:

(i) a conjugated anti-CD74 antibody or antigen-binding fragment thereof and an unconjugated anti-CD20 antibody or antigen binding fragment thereof, or

(ii) a conjugated anti-CD20 antibody or antigen-binding fragment thereof and an unconjugated anti-CD74 antibody or antigen-binding fragment thereof,

wherein the unconjugated anti-CD20 or anti-CD74 is a maintenance therapy to keep proliferating tumor cells from target escape.

38. A method for treating a B-cell related malignancy disease comprising administering to a human a therapeutic composition comprising:

(a) a pharmaceutically acceptable vehicle containing unconjugated anti-CD20 antibody, or an antigen-binding fragment thereof, or unconjugated single chain antibody fusion protein, said antibody fusion protein comprising a recombinantly produced antigen-binding molecule in which two or more of the same or different single-chain antibodies, or two or more of the same or different antigen-binding fragments are linked,

wherein said unconjugated antibody or antigen-binding fragment thereof or said unconjugated fusion protein targets CD20, and said fusion protein or antigen-binding fragment comprises the variable domains, or the CDRs of the heavy and light chains of said CD20 antibody; and

(b) a pharmaceutically acceptable vehicle containing a conjugated humanized monoclonal antibody or antigen-binding fragment thereof that binds CD74, said antibody or antigen-binding fragment thereof being conjugated to doxorubicin

wherein (a) and (b) are administered concurrently or sequentially.

39. The method of claim 38, wherein the B-cell related malignancy disease is a leukemia.

42. The method of claim 38, wherein the B-cell-related malignancy disease is a B-cell lymphoma, B-cell acute lymphocytic leukemia, B-cell chronic lymphocytic leukemia, or multiple myeloma.

43. The method of claim 38, wherein the B-cell-related malignancy disease is non-Hodgkin'"'"'s lymphoma (NHL).

44. The method of claim 38, wherein the B-cell-related malignancy disease is multiple myeloma.