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1. WO2006094192 - HUMANIZED L243 ANTIBODIES

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[ EN ]

What is claimed is:
1. A humanized L243 antibody comprising a heavy chain variable domain wherein the CDRl, CDR2, and CDR3 regions and framework residues 27, 38, 46, 68 and 91 of said variable domain are from the mouse monoclonal antibody mL243 heavy chain and the remainder of the immunoglobulin framework domains are from one or more human heavy chains, wherein the antibody has the ability to bind to at least one epitope of HLA-DR on HLA-DR+ cells, and wherein said antibody causes or leads to killing of said cells in a manner where neither cytotoxic addends nor immunological effector
mechanisms are needed for said killing.
2. A humanized L243 antibody comprising a light chain variable domain wherein the CDRl, CDR2, and CDR3 regions and framework residues 37, 39, 48 and 49 of said variable domain are from the mouse monoclonal antibody mL243 light chain and the remainder of the immunoglobulin framework domains are from one or more human light chains, wherein the antibody has the ability to bind to at least one epitope of HLA-DR on HLA-DR+ cells, and wherein said antibody causes or leads to killing of said cells in a manner where neither cytotoxic addends nor immunological effector mechanisms are needed for said killing.
3. A humanized L243 antibody comprising a heavy chain variable domain and a light chain variable domain, wherein the CDRl, CDR2, and CDR3 regions and framework residues 27, 38, 46, 68 and 91 of said heavy chain variable domain are from the mouse monoclonal antibody mL243 heavy chain and the remainder of the
immunoglobulin heavy chain framework domains are from one or morehuman heavy chains, wherein the CDRl, CDR2, and CDR3 regions and framework residues 37, 39, 48 and 49 of said light chain variable domain are from the mouse monoclonal antibody mL243 light chain and the remainder of the immunoglobulin light chain framework domains are from one or more human light chains, wherein the antibody has the ability to bind to at least one epitope of HLA-DR on HLA-DR+ cells, and wherein said antibody causes or leads to killing of said cells in a manner where neither cytotoxic addends nor immunological effector mechanisms are needed for said killing.
4. A pharmaceutical composition comprising an antibody according to claim

3.
5. The composition of claim 4, further comprising one or more additional binding molecules which specifically bind to one or more tumor associated antigens, wherein the additional binding molecule is given before, with, or after the composition of claim 3.

6. A method of treating a condition associated with undesired proliferation of cells expressing HLA-DR comprising administering to a patient suffering from said disease an effective amount of a composition according to claim 3.
7. The method according to claim 6, wherein said cells are lymphoid cells.
8. The method of claim 6, wherein said cells are solid cancer cells.
9. The method of claim 7, wherein the solid cancer cells are selected from a group consisting of carcinomas, melanomas, sarcomas, gliomas, and skin cancers.
10. The method according to claim 6, wherein the condition is an autoimmune disease.
11. The method according to claim 6, wherein the condition is a leukemia or lymphoma.
12. The method according to claim 6, wherein the condition is a metabolic disease.
13. The method according to claim 6, wherein the conditon is a
neurodegenerative disease.
14. The method according to claim 6, wherein the condition is selected from immune-dysregulatory disorders.
15. A pharmaceutical composition comprising the humanized L243 antibody according to claim 3, conjugated to one or more peptides, lipids, polymeric carriers, micelles, nanoparticles, or combinations thereof; and one or more effectors.
16. The composition of claim 15, wherein the composition is an
immunoconjugate.
17. The composition of claim 15, wherein the antibody is conjugated to one or more lipids.
18. The composition of claim 15, further comprising one or more additional binding molecules which specifically bind to one or more tumor associated antigens¤ä
19. The composition of claim 15, wherein the humanized L243 antibody has at least one specificity for HLA-DR, wherein the remaining specificity is for a peptide that binds an additional binding molecule which specifically bind to one or more tumor associated antigens.
20. The composition of claim 15, wherein the effector comprises a therapeutic agent or a diagnostic agent.
21. The composition of claim 15, wherein the effector comprises a drug, a prodrug, a toxin, an enzyme, a radioisotope, an immunomodulator, a cytokine, a hormone, a binding molecule, an oligonucleotide, an interference RNA, a photodynamic agent, or mixtures thereof.
22. The composition of claim 15, wherein the effector comprises FUdR, FUdR-dO, or mixtures thereof.
23. The composition of claim 15, further comprising cations selected from

Group II, Group III, Group IV, Group V, transition, lanthanide or actinide metal cations, or mixtures thereof.
24. The composition of claim 15, further comprising cations selected from Tc, Re, Bi, Cu, As, Ag, Au, At, Pb, or mixtures thereof.
25. The composition of claim 15, further comprising NOTA, DOTA, DTPA,

TETA, Tscg-Cys, Tsca-Cys, or mixtures thereof.
26. The composition of claim 15, wherein the effector comprises a
radionuclide.
27. The composition of claim 15, wherein the effector comprises an enzyme. 28. The composition of claim 15, wherein the effector comprises an immunomodulator.
29. The composition of claim 15, wherein the effector comprises an anti-angiogenic agent.
30. The composition of claim 15, wherein the antibody is conjugated to one or more therapeutic agents, diagnostic agents, or mixtures thereof.
31. A method of treating a patient using the composition of claim 15.
32. The method of claim 31 , wherein the composition is administered intravenously, subcutaneously, or intramuscularly at a dose of 20-2000 mg.
33. The method of claim 31 , wherein the composition comprises one or more agents for photodynamic therapy.
34. The method of claim 33, wherein the agent for photodynamic therapy is a photosensitizer.
35. The method of claim 31 , wherein the composition comprises one or more diagnostic agents.
36. The method of claim 31, wherein the composition comprises a diagnostic agent.
37. The method of claim 36, wherein the diagnostic agent is used for performing positron emission tomograph (PET).

38. The method of claim 36, wherein the diagnostic agent comprises one or more image enhancing agents and the method further comprises performing magnetic resonance imaging (MRI).
39. The method of claim 31 , wherein the composition comprises one or more radiopaque agents or contrast agents for X-ray or computed tomography (CT).
40. The method of claim 31 , further comprising administering an additional composition which comprises a therapeutic agent, a diagnostic agent, or mixtures thereof.

41. The method claim 40, wherein the additional composition comprises:
an immunoconjugate which a humanized L243 antibody conjugated to one or more lipids, polymeric carriers, micelles, nanoparticles, or combinations thereof; and one or more effectors.
42. The method of claim 41 , wherein the humanized L243 antibody or fragment thereof is conjugated to the therapeutic agent, the diagnostic agent, or mixtures thereof by chemical conjugation or genetic fusion.
43. The method of claim 40, wherein the composition is administered before, during, simultaneously, or after the administration of the additional composition.
44. A kit comprising the composition of claim 30.
45. A method of treating a disorder in a subject, comprising administering to said subject a "naked" polyvalent protein complex, comprising three binding sites wherein at least one binding site is composed of any one of the hL243 variable domains as described in claim 3 and one or more binding sites for a tumor associated.
46. The method of claim 45, wherein the disorder is a neoplastic, autoimmune, or immune dysregulation disorder, metabolic disorder, or neurodegenerative disease.
47. A method of treating a condition associated with proliferation of cells expressing HLA-DR comprising (A) administering an effective amount of a bispecific antibody or antibody fragment comprising at least one arm that specifically binds HLA-DR and at least one other arm that specifically binds a targetable conjugate, wherein said one arm that binds HLA-DR is an hL243 antibody or fragment thereof and wherein said targetable conjugate comprises a hapten moiety and a therapeutic agent; and (B) administering said targetable conjugate to a patient with said condition.
48. A method of treating a condition associated with proliferation of cells expressing HLA-DR comprising administering to a subject with said condition an effective amount of a bispecific antibody or antibody fragment comprising one arm that specifically binds HLA-DR and one arm that binds to a tumor-associated antigen, wherein said one arm that binds HLA-DR is an hL243 antibody or fragment thereof.
49. The method of claim 48, wherein said condition comprises a B-cell malignancy.
50. The method of claim 48, wherein said tumor-associated antigen is CD20.

51. A method of treating a condition associated with proliferation of cells expressing HLA-DR comprising (A) administering to a subject having said condition an effective amount of a antibody or antibody fragment that specifically binds HLA-DR, wherein said HLA-DR specific antibody is an hL243 antibody or fragment thereof; and (B) administering to said subject before, after or simultaneously with said anti-HLA-DR antibody an effective amount of an antibody or antibody fragment that binds to a tumor-associated antigen.
52. The method of claim 51 , wherein said condition comprises a B-cell malignancy.
53. The method of claim 51 , wherein said anti-tumor-associated antigen antibody or antibody fragment comprises a humanized antibody or antibody fragment. 54. The method of claim 51 , wherein said tumor-associated antigen is CD20.