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1. CA2599734 - HUMANIZED L243 ANTIBODIES

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CLAIMS:
1. A humanized L243 antibody or antigen-binding fragment thereof, comprising heavy chain variable domain complementarity determining region (CDR) sequences CDR1 (NYGMN, residues 31 to 35 of SEQ ID NO: 4), CDR2 (WINTYTREPTYADDFKG, residues 50 to 66 of SEQ ID NO:4), and CDR3 (DITAVVPTGFDY, residues 99 to 110 of SEQ ID NO:4) and heavy chain framework residues F27, K38, K46, A68, and F91 and light chain variable domain CDR sequences CDR1 (RASENIYSNLA, residues 24 to 34 of SEQ ID NO:2), CDR2 (AASNLAD, residues 50 to 56 of SEQ ID NO:2), and CDR3 (QHFWTTPWA, residues 89 to 97 of SEQ ID NO:2) and light chain framework residues R37, K39, V48 and F49, wherein the remainder of the humanized L243 antibody framework region and constant region sequences are from one or more human antibodies, and wherein the humanized L243 antibody has the ability to bind to HLA-DR on HLA-DR+ cells.
2. The humanized antibody or antigen-binding fragment thereof of claim 1, wherein the humanized L243 antibody has about 2-fold higher affinity than the murine L243 antibody for HLA-DR.
3. The humanized antibody or antigen-binding fragment thereof of claim 1 or
wherein the humanized L243 antibody or fragment thereof comprises human IgG4 constant region sequences.
4. The humanized antibody or antigen-binding fragment thereof of claim 3, further comprising a Ser241 Pro point mutation in the hinge region of the antibody or fragment thereof.
5. The humanized antibody or antigen-binding fragment thereof of claim 1 or
wherein the humanized L243 antibody comprises the hL243VK amino acid sequence SEQ ID NO:6 and the hL243VH amino acid sequence SEQ ID NO:8.
6. The humanized antibody or antigen-binding fragment thereof of claim 1 or
wherein the humanized L243 antibody has a lower dissociation constant for HLADR+ cells than the murine L243 antibody.
7. The humanized antibody or antigen-binding fragment thereof of any one of
claims 1 to 6, wherein the humanized L243 antibody or fragment thereof is a naked antibody or fragment thereof.
8. The humanized antibody or antigen-binding fragment thereof of any one of
claims 1 to 6, wherein the humanized L243 antibody or fragment thereof is conjugated to at least one therapeutic or diagnostic agent.
9. The humanized antibody or antigen-binding fragment thereof of claim 8, wherein the therapeutic agent is selected from the group consisting of antibodies, antibody fragments, drugs, chemotherapeutic agents, toxins, enzymes, nucleases, hormones, hormone antagonists, immunomodulators, cytokines, oligonucleotides, interference RNA, chelators, boron compounds, photoactive agents, dyes and radioisotopes.
10. The humanized antibody or antigen-binding fragment thereof of claim 9, wherein the chemotherapeutic agent is a taxane, a nitrogen mustard, an ethylenimine, an alkyl sulfonate, a nitrosourea, a triazene, a folic acid analog, a pyrimidine analog, a purine analog, an antisense oligonucleotide, an interference RNA, an antibiotic, a platinum coordination complex, a COX-2 inhibitor, an apoptotic agent, a substituted urea, a methyl hydrazine, a steroid, a progestin, an estrogen, an antiestrogen, an androgen, actinomycin, azaribine, anastrozole, azacytidine, bleomycin, bryostatin- 1, busulfan, carmustine, Celebrex™, chlorambucil, cisplatin, irinotecan (CPT- 11), carboplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dacarbazine, dactinomycin, daunorubicin, dexamethasone, diethyistilbestrol, doxorubicin, ethinyl estradiol, estramustine, etoposide, floxuridine, fludarabine, flutamide, 5-fluorouracil, fluoxymesterone, gemcitabine, hydroxyprogesterone caproate, hydroxyurea, idarubicin, ifosfamide, L-asparaginase, leucovorin, lomustine, mechlorethamine, medroprogesterone acetate, megestrol acetate, melphalan, mercaptopurine,
methotrexate, mitoxantrone, mitomycin, mitotane, oxaliplatin, phenyl butyrate, prednisone, procarbazine, paclitaxel, pentostatin, semustine, streptozocin, SN-38, tamoxifen, taxanes, taxol, testosterone propionate, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vinblastine, vinorelbine or vincristine.
11. The humanized antibody or antigen-binding fragment thereof of claim 9, wherein the toxin is ricin, abrin, ribonuclease, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, or Pseudomonas endotoxin.
12. The humanized antibody or antigen-binding fragment thereof of claim 9, wherein the immunomodulator is a cytokine, a stem cell growth factor, a lymphotoxin, a tumor necrosis factor (TNF), TNF-alpha, a hematopoietic factor, an interleukin, IL-1, IL-2, IL-3, IL-6, IL- 10, IL- 12, IL- 18, IL-21, a colony stimulating factor, G-CSF, GM-CSF, interferon-alpha, -beta or -gamma, the stem cell growth factor designated "S1 factor", erythropoietin or thrombopoietin.
13. The humanized antibody or antigen-binding fragment thereof of claim 12,
wherein the cytokine is interferon-alpha, interferon-beta, interferon-gamma or GM-CSF.
14. The humanized antibody or antigen-binding fragment thereof of claim 9, wherein the radioisotope is In-111, Lu-177, Bi-212, Bi-213, At-211, Cu-62, Cu64, Cu-67, Y90, I-125, I-131, P-32, P-33, Sc-47, Ag-111, Ga-67, Pr-142, Sm-153, Th-161, Dy166, Ho166, Re-186, Re-188, Re-189, Pb-212, Ra-223, Ac-225, Fe-59, Se-75, As-77, Sr89, Mo-99, Rh-105, Pd-109, Pr-143, Pm-149, Er-169, Ir-194, Au-198, Au-199, Ac-225 or Pb
15. A bispecific antibody or antigen-binding fragment thereof comprising at least one first antibody or fragment thereof according to any one of claims 1 to 14 and at least one second antibody or fragment thereof.
16. The bispecific antibody or fragment thereof of claim 15, wherein the second antibody or second antibody fragment binds to a tumor-associated antigen.
17. The bispecific antibody or fragment thereof of claim 16, wherein the tumorassociated antigen is selected from the group consisting of A3, antigen specific for A33 antibody, BrE3-antigen, CD1, CD1a, CD3, CD5, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD30, CD45, CD74, CD79a, CD80, HLA-DR, NCA95, NCA90, HCG, CEA (CEACAM-5), CEACAM-6, CSAp, EGFR, EGP-1, EGP-2, Ep-CAM, Ba 733, HER2/neu, hypoxia inducible factor (HIF), KC4-antigen, KS-1 antigen, KS 1-4, Le-Y, macrophage inhibition factor (MIF), MAGE, MUC1, MUC2, MUC3, MUC4, MUC16, PAM-4-antigen, PSA, PSMA, RS5, S100, TAG-72, p53, tenascin, IL-6, IL-8, insulin growth factor1 (IGF-1), Tn antigen, Thomson-Friedenreich antigens, tumor necrosis antigens, VEGF, 17- 1 A-antigen, an angiogenesis marker, ED-B fibronectin, an oncogene marker, an oncogene product, Ia, HM1.24, VEGF, ILGF, placental growth factor and carbonic anhydrase IX.
18. The bispecific antibody or fragment thereof of claim 15, wherein the second antibody or second antibody fragment binds to a targetable conjugate that comprises at least one hapten moiety and at least one therapeutic agent.
19. The humanized antibody or antigen-binding fragment thereof of any one of claims 1 to 14, wherein the antibody or fragment induces apoptosis in cancer cell lines that are resistant to anti-CD20 antibodies.
20. The humanized antibody or antigen-binding fragment thereof of claim 19,
wherein the antibody or fragment induces apoptosis in the Namalwa human lymphoma cell line.
21. A pharmaceutical composition comprising the humanized antibody or antigenbinding fragment thereof according to any one of claims 1 to 6 and a pharmaceutically acceptable excipient.
22. The composition of claim 21, wherein the humanized antibody or fragment
thereof is conjugated to one or more peptides, lipids, polymeric carriers, micelles, nanoparticles, or a combination thereof
23. The composition of claim 21, further comprising at least one therapeutic agent.
24. The composition of claim 23, wherein the therapeutic agent is a drug, a
prodrug, a toxin, an enzyme, a radioisotope, an immunomodulator, a cytokine, a hormone, a second antibody or antigen binding fragment thereof, an oligonucleotide, an interference RNA, a photodynamic agent, or a combination thereof.
25. The composition of claim 21, wherein the humanized antibody or antigenbinding fragment thereof is conjugated to a chelator selected from the group consisting of NOTA, DOTA, DTPA, TETA, Tscg-Cys, and Tsca-Cys, or a combination thereof.
26. A kit comprising the composition according to claim 23 or 24 and a buffer.
27. Use of the humanized L243 antibody or antigen-binding fragment thereof of claim 1 or 2 for preparing a medicament for treating a disease associated with proliferation of cells expressing HLA-DR (HLA-DR+ cells).
28. The use of claim 27, wherein the humanized L243 antibody or fragment comprises human IgG4 constant region sequences.
29. The use of claim 28, wherein the humanized L243 antibody or fragment thereof further comprises a Ser241 Pro point mutation in the hinge region of the antibody or fragment thereof.
30. The use of claim 27, wherein the humanized L243 antibody comprises the hL243VK amino acid sequence SEQ ID NO:6 and the hL243VH amino acid sequence SEQ ID NO:8.
31. The use of any one of claims 27 to 30, wherein the disease is a cancer, an autoimmune disease, a leukemia, a lymphoma, a metabolic disease, a neurodegenerative disease or an immune-dysregulatory disease.
32. The use of any one of claims 27 to 31, wherein the humanized L243 antibody or fragment thereof is a naked antibody or fragment thereof.
33. The use of any one of claims 27 to 31, wherein the humanized L243 antibody or fragment thereof is conjugated to at least one therapeutic or diagnostic agent.
34. The use of claim 33, wherein the therapeutic agent is selected from the group consisting of antibodies, antibody fragments, drugs, chemotherapeutic agents, toxins, enzymes, nucleases, hormones, hormone antagonists, immunomodulators, cytokines, oligonucleotides, interference RNA, chelators, boron compounds, photoactive agents, dyes and radioisotopes.
35. Use of the humanized L243 antibody or antigen-binding fragment thereof of any one of claims 1 to 14 for treating a disease associated with proliferation of cells expressing HLA-DR (HLA-DR+ cells).
36. A composition comprising a pharmaceutically acceptable carrier and the humanized L243 antibody or antigen-binding fragment thereof of any one of claims 1 to 14 for use in the treatment of a disease associated with proliferation of cells expressing HLA-DR (HLA-DR+ cells).