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1. EP1853313 - HUMANIZED L243 ANTIBODIES

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Claims

1. A humanized L243 antibody or antigen-binding fragment thereof binding to at least one epitope of HLA-DR on HLA-DR+ cells and comprising a heavy chain variable domain and a light chain variable domain, wherein the CDR1 (NYGMN), CDR2 (WINTYTREPTYADDFKG), and CDR3 (DTTAVVPTGFDY) regions and framework residues 27, 38, 46, 68 and 91 of said heavy chain variable domain using the Kabat numbering system are from the mouse monoclonal antibody mL243 heavy chain and the remainder of the immunoglobulin heavy chain framework domains are from one or more human heavy chains, wherein the CDR1 (RASENIYSNLA), CDR2 (AASNLAD), and CDR3 (QHFWTTPWA) regions and framework residues 37, 39, 48 and 49 of said light chain variable domain using the Kabat numbering system 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.
  2. The humanized L243 antibody or antigen-binding fragment thereof of claim 1, wherein the humanized L243 antibody or antigen-binding fragment thereof comprises human IgG4 constant region sequences.
  3. The humanized L243 antibody or antigen-binding fragment thereof of claim 2, wherein the humanized L243 antibody or antigen-binding fragment thereof comprises a Ser241 Pro point mutation.
  4. A pharmaceutical composition comprising an antibody according to any one of claims 1 to 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 humanized L243 antibody or antigen-binding fragment thereof of any one of claims 1 to 3.
  6. A composition comprising the humanized L243 antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, for use in a treatment of a condition associated with undesired proliferation of cells expressing HLA-DR.
  7. The composition for use of claim 6, wherein said cells are lymphoid or myeloid cells.
  8. The composition for use of claim 6, wherein said cells are solid cancer cells.
  9. The composition for use of claim 6, wherein the condition is an autoimmune disease.
  10. The composition for use of claim 6, wherein the condition is a leukemia or lymphoma.
  11. The composition for use of claim 6, wherein the condition is amyloidosis.
  12. The composition for use of claim 6, wherein the condition is a neurodegenerative disease.
  13. The composition for use of claim 6, wherein the condition is selected from immune-dysregulatory disorders.
  14. A pharmaceutical composition comprising the humanized L243 antibody according to any one of claims 1 to 3, conjugated to one or more peptides, lipids, polymeric carriers, micelles, nanoparticles, or combinations thereof; and one or more effectors.
  15. The composition of claim 14, wherein the composition is an immunoconjugate.
  16. The composition of claim 14, wherein the antibody is conjugated to one or more lipids.
  17. The composition of claim 14, further comprising one or more additional binding molecules which specifically bind to one or more tumor-associated antigens.
  18. The composition of claim 14, 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.
  19. The composition of claim 14, wherein the effector comprises a therapeutic agent or a diagnostic agent.
  20. The composition of claim 14, 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.
  21. The composition of claim 14, wherein the effector comprises FUdR, FUdR-dO, or mixtures thereof.
  22. The composition of claim 14, further comprising cations selected from Group II, Group III, Group IV, Group V, transition, lanthanide or actinide metal cations, or mixtures thereof.
  23. The composition of claim 14, further comprising cations selected from Tc, Re, Bi, Cu, As, Ag, Au, At, Pb, or mixtures thereof.
  24. The composition of claim 14, further comprising NOTA, DOTA, DTPA, TETA, Tscg-Cys, Tsca-Cys, or mixtures thereof.
  25. The composition of claim 14, wherein the effector comprises a radionuclide.
  26. The composition of claim 14, wherein the effector comprises an enzyme.
  27. The composition of claim 14, wherein the effector comprises an immunomodulator.
  28. The composition of claim 14, wherein the effector comprises an anti-angiogenic agent.
  29. The composition of claim 14, wherein the antibody is conjugated to one or more therapeutic agents, diagnostic agents, or mixtures thereof.
  30. The composition for use of claim 6, wherein the humanized L243 antibody is conjugated to one or more peptides, lipids, polymeric carriers, micelles, nanoparticles, or combinations thereof and the composition further comprises one or more effectors.
  31. The composition for use of claim 30, wherein the composition comprises one or more agents for photodynamic therapy.
  32. The composition for use of claim 31, wherein the agent for photodynamic therapy is a photosensitizer.
  33. The composition for use of claim 30, wherein the composition comprises one or more diagnostic agents.
  34. The composition for use claim 33, wherein the diagnostic agent comprises one or more MRI image enhancing agents.
  35. The composition for use of claim 30, wherein the composition comprises one or more radiopaque agents or contrast agents for X-ray or computed tomography (CT).
  36. The composition for use of claim 30, further comprising an additional composition which comprises a therapeutic agent, a diagnostic agent, or mixtures thereof.
  37. The composition for use of claim 36, wherein the composition is administered before, during, simultaneously, or after the administration of the additional composition.
  38. A kit comprising the composition of claim 29.
  39. The composition for use of claim 6, wherein the composition comprises a "naked" polyvalent protein complex, comprising three binding sites wherein at least one binding site is composed of a humanized L243 antibody and one or more binding sites bind to a tumor-associated antigen.
  40. The composition for use of claim 39, wherein the condition is a neoplastic, autoimmune, or immune dysregulation disorder, metabolic disorder, or neurodegenerative disease.
  41. The composition for use of claim 6, wherein the composition comprises a bispecific antibody or antibody fragment comprising at least one arm that comprises a humanized L243 antibody or fragment thereof and at least one other arm that specifically binds a targetable conjugate wherein said targetable conjugate comprises a hapten moiety and a therapeutic agent.
  42. The composition for use of claim 6, wherein the composition comprises a bispecific antibody or antibody fragment comprising a humanized L243 antibody or fragment thereof and one arm that binds to a tumor-associated antigen.
  43. The composition for use of claim 42, wherein said condition comprises a B-cell or T-cell malignancy.
  44. The composition for use of claim 42, wherein said tumor-associated antigen is CD20.
  45. The composition for use of claim 6, wherein said composition further comprises an antibody or antibody fragment that binds to a tumor-associated antigen.
  46. The composition for use of claim 45, wherein said condition comprises a B-cell malignancy.
  47. The composition for use of claim 45, wherein said antibody or antibody fragment that binds to a tumor-associated antigen comprises a humanized antibody or antibody fragment.
  48. The composition for use of claim 45, wherein said tumor-associated antigen is CD20.
  49. The composition for use of claim 44, wherein said arm that binds to CD20 is a humanized A20 (hA20) antibody or fragment thereof or rituximab.
  50. The composition for use of claim 48, wherein said CD20 binding antibody or fragment is an hA20 antibody or fragment thereof or rituximab.
  51. The composition for use of claim 6, wherein the condition is organ transplantation.
  52. The composition for use of claim 49, wherein said arm that binds to CD20 is rituximab and said humanized L243 antibody or fragment thereof is an IgG4.
  53. The composition for use of claim 50, wherein said arm that binds to CD20 is rituximab and said humanized L243 antibody or fragment thereof is an IgG4.
  54. The antibody of any one of claims 1 to 3, 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.