Anti-mn antibodies and methods of using same

Abstract

The invention provides antibodies having an antigenic binding site specifically directed against an MN protein, and methods of using such antibodies in treating and diagnosing an MN-related disorder.

1 - 3 . (canceled) 
     
     
         4 . An antibody or antibody fragment having an antigenic binding site specifically directed against an MN protein, wherein the antigenic binding site comprises a set of CDR sequences
 [3ef2] SEQ ID NOS: 58, 64, 71, 107, 109, and 111;   [1e4] SEQ ID NOS: 59, 65, 72, 107, 109, and 111;   [3a4] SEQ ID NOS: 60, 66, 73, 108, 110, and 112;   [3ab4] SEQ ID NOS: 61, 67, 74, 87, 91, and 95;   [3ah10] SEQ ID NOS: 61, 68, 75, 88, 92, and 96;   [3bb2] SEQ ID NOS: 62, 69, 76, 98, 100, and 102;   [1aa1] SEQ ID NOS: 77, 78, 79, 86, 90, and 94;   [5a6] SEQ ID NOS: 80, 82, 84, 99, 101, and 103; and   [5aa3] SEQ ID NOS: 81, 83, 85, 104, 105, and 106.   
     
     
         5 - 6 . (canceled) 
     
     
         7 . The antibody or antibody fragment according to  claim 4 , wherein the antibody or antibody fragment binds to the MN protein with a dissociation constant of about 0.15 nM to about 50 nM. 
     
     
         8 . The antibody or antibody fragment according to  claim 4 , wherein the antibody is an IgG. 
     
     
         9 . The antibody or antibody fragment according to  claim 4 , wherein the antibody is an IgG1, IgG2a, IgG2b, IgG3, IgM, IgD, IgE, IgA, IgM Fab fragment, F(ab′) 2  fragment, scFv fragment, Fv fragment, a diabody, linear antibody, single-chain antibody, bispecific antibody, chimeric antibody, or multispecific antibody. 
     
     
         10 . The antibody or antibody fragment according to  claim 4 , wherein the antibody or antibody fragment is humanized. 
     
     
         11 . The antibody or antibody fragment according to  claim 4 , wherein the CDR1, CDR2, and CDR3 are non-human. 
     
     
         12 . A composition comprising an antibody or antibody fragment thereof according to  claim 4  and one or more pharmaceutical auxiliary substance. 
     
     
         13 - 19 . (canceled) 
     
     
         20 . A composition reactive against MN protein comprising an antibody or antibody fragment having an antigenic binding site specifically directed against an MN protein conjugated to a cytotoxic agent, wherein the antigenic binding site comprises a set of CDR sequences
 [3ef2] SEQ ID NOS: 58, 64, 71, 107, 109, and 111;   [1e4] SEQ ID NOS: 59, 65, 72, 107, 109, and 111;   [3a4] SEQ ID NOS: 60, 66, 73, 108, 110, and 112;   [3ab4] SEQ ID NOS: 61, 67, 74, 87, 91, and 95;   [3ah10] SEQ ID NOS: 61, 68, 75, 88, 92, and 96;   [3bb2] SEQ ID NOS: 62, 69, 76, 98, 100, and 102;   [1aa1] SEQ ID NOS: 77, 78, 79, 86, 90, and 94;   [5a6] SEQ ID NOS: 80, 82, 84, 99, 101, and 103; and   [5aa3] SEQ ID NOS: 81, 83, 85, 104, 105, and 106.   
     
     
         21 - 22 . (canceled) 
     
     
         23 . The composition according to  claim 20 , wherein the cytotoxic agent is selected from the group consisting of: monomethylauristatin-E or functional analog thereof, monomethylauristatin-F or functional analog thereof, aplidin, azaribine, anastrozole, azacytidine, bleomycin, bortezomib, bryostatin-1, busulfan, calicheamycin, camptothecin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatin, irinotecan (CPT-1 1), SN-38, carboplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunomycin glucuronide, daunorubicin, dexamethasone, diethylstilbestrol, doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, ethinyl estradiol, estramustine, etoposide, etoposide glucuronide, etoposide phosphate, floxuridine (FUdR), 3′,5′-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, fluorouracil, fluoxymesterone, gemcitabine, hydroxyprogesterone caproate, hydroxyurea, idarubicin, ifosfamide, L-asparaginase, leucovorin, lomustine, mechlorethamine, medroprogesterone acetate, megestrol acetate, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, phenyl butyrate, prednisone, procarbazine, paclitaxel, pentostatin, PSI-341, semustine streptozocin, tamoxifen, taxanes, taxol, testosterone propionate, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, velcade, vinblastine, vinorelbine, vincristine, ricin, abrin, ribonuclease, onconase, rapLR1, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin,  Pseudomonas exotoxin, Pseudomonas  endotoxin, and combinations thereof. 
     
     
         24 . The composition according to  claim 20 , wherein the cytotoxic agent is monomethylauristatin-E or functional analog thereof. 
     
     
         25 . The composition according to  claim 20 , wherein the antibody or antibody fragment binds to the MN protein with a dissociation constant of about 0.15 nM to about 50 nM. 
     
     
         26 . The composition according to  claim 20 , wherein the antibody is an IgG. 
     
     
         27 . The composition according to  claim 20 , wherein the antibody or antibody fragment is an IgG1, IgG2a, IgG2b, IgG3, IgM, IgD, IgE, IgA, or IgM isotype, an Fab fragment, F(ab′)2 fragment, scFv fragment, Fv fragment, a diabody, linear antibody, single-chain antibody, bispecific antibody, a chimeric antibody or multispecific antibody. 
     
     
         28 . The composition according to  claim 20 , wherein the antibody or antibody fragment humanized. 
     
     
         29 . The antibody or antibody fragment according to  claim 20 , wherein the CDR1, CDR2, and CDR3 are non-human. 
     
     
         30 - 32 . (canceled) 
     
     
         33 . A composition for treating a subject having an MN-related cancer, comprising an anti-cancer agent and an antibody or antibody fragment thereof having an antigenic binding site specifically directed against an MN protein conjugated to a cytotoxic agent, wherein the antigenic binding site comprises a set of CDR sequences
 [3ef2] SEQ ID NOS: 58, 64, 71, 107, 109, and 111;   [1e4] SEQ ID NOS: 59, 65, 72, 107, 109, and 111;   [3a4] SEQ ID NOS: 60, 66, 73, 108, 110, and 112;   [3ab4] SEQ ID NOS: 61, 67, 74, 87, 91, and 95;   [3ah10] SEQ ID NOS: 61, 68, 75, 88, 92, and 96;   [3bb2] SEQ ID NOS: 62, 69, 76, 98, 100, and 102;   [1aa1] SEQ ID NOS: 77, 78, 79, 86, 90, and 94;   [5a6] SEQ ID NOS: 80, 82, 84, 99, 101, and 103; and   [5aa3] SEQ ID NOS: 81, 83, 85, 104, 105, and 106.   
     
     
         34 - 35 . (canceled) 
     
     
         36 . The composition according to  claim 33 , wherein the anti-cancer agent is selected from the group consisting of: capecitabine, bleomycin, docetaxel (Taxotere), doxorubicin, edatrexate, erlotinib (Tarceva), etoposide, finasteride (Proscar), flutamide (Eulexin), gemcitabine (Gemzar), genitinib (Irresa), goserelin acetate (Zoladex), granisetron (Kytril), imatinib (Gleevec), irinotecan (Campto/Camptosar), ondansetron (Zofran), paclitaxel (Taxol), pegaspargase (Oncaspar), pilocarpine hydrochloride (Salagen), porfimer sodium (Photofrin), interleukin-2 (Proleukin), rituximab (Rituxan), topotecan (Hycamtin), trastuzumab (Herceptin), Triapine, vincristine, vinorelbine tartrate (Navelbine), and therapeutic antibodies or fragments thereof. 
     
     
         37 . The composition according to  claim 33 , wherein the anti-cancer agent is an anti-angiogenic agent selected from the group consisting of angiostatin, bevacizumab (Avastin®), sorafenib (Nexavar®), baculostatin, canstatin, maspin, anti-VEGF antibodies or peptides, anti-placental growth factor antibodies or peptides, anti-Flk-1 antibodies, anti-Flt-1 antibodies or peptides, laminin peptides, fibronectin peptides, plasminogen activator inhibitors, tissue metalloproteinase inhibitors, interferons, interleukin 12, IP-10, Gro-β, thrombospondin, 2-methoxyoestradiol, proliferin-related protein, carboxiamidotriazole, CM101, Marimastat, pentosan polysulphate, angiopoietin 2, interferon-alpha, herbimycin A, PNU145156E, 16K prolactin fragment, Linomide, thalidomide, pentoxifylline, genistein, TNP-470, endostatin, paclitaxel, accutin, cidofovir, vincristine, bleomycin, AGM-1470, platelet factor 4 and minocycline. 
     
     
         38 . The composition according to  claim 33 , wherein the anti-cancer agent is an agent that blocks or inhibits a multi-drug resistance phenotype selected from the group consisting of tamoxifen, verapamil and cyclosporin A. 
     
     
         39 . The composition according to  claim 33 , wherein the cytotoxic agent is monomethylauristatin-E or functional analog thereof. 
     
     
         40 . (canceled) 
     
     
         41 . The composition according to  claim 33 , wherein the antibody or antibody fragment binds to the MN protein with a dissociation constant of about 0.15 nM to about 50 nM. 
     
     
         42 . The composition according to  claim 33 , wherein the antibody is an IgG. 
     
     
         43 . The composition according to  claim 33 , wherein the antibody or antibody fragment is an IgG1, IgG2a, IgG2b, IgG3, IgM, IgD, IgE, IgA, or IgM isotype, a Fab fragment, F(ab′) 2  fragment, scFv fragment, Fv fragment, a diabody, linear antibody, single-chain antibody, bispecific antibody, chimeric antibody or multispecific antibody. 
     
     
         44 . The composition according to  claim 33 , wherein the antibody or antibody fragment is humanized. 
     
     
         45 . The composition according to  claim 33 , wherein the CDR1, CDR2, and CDR3 are non-human. 
     
     
         46 - 49 . (canceled) 
     
     
         50 . The composition according to  claim 33 , wherein the cancer is in the form of a solid tumor. 
     
     
         51 . The composition according to  claim 50 , wherein the solid tumor is in or originating from the breast, respiratory tract, lung, brain, reproductive organ, digestive tract, colon, urinary tract, kidney, esophagus, cervix, eye, liver, skin, head, neck, thyroid, and parathyroid. 
     
     
         52 . A method of diagnosing an MN-related disorder characterized by abnormal MN levels comprising comparing the level of MN in a suspected diseased tissue or cell with the level of MN in a corresponding healthy tissue or cell, wherein an abnormal MN level in the suspected diseased tissue or cell is an indication of an MN-related disorder, said step of comparing further comprising detecting the level of MN in the diseased tissue and the healthy tissue with the antibody or antibody fragment according to  claim 4 . 
     
     
         53 . The method according to  claim 52 , wherein the MN-related disorder is a cancer. 
     
     
         54 . The method according to  claim 52 , wherein the cancer is in the form of a solid tumor. 
     
     
         55 . The method according to  claim 52 , wherein the solid tumor is in or originating from the breast, respiratory tract, lung, brain, reproductive organ, digestive tract, colon, urinary tract, kidney, esophagus, cervix, eye, liver, skin, head, neck, thyroid, and parathyroid. 
     
     
         56 . The method according to  claim 52 , wherein the step of comparing further comprises the steps of:
 a) detecting the level of MN protein in the healthy tissue;   b) detecting the level of MN protein in the suspected diseased tissue; and   c) comparing the levels of MN protein from (a) and (b),   
       wherein an elevated level of MN protein in the suspected diseased tissue as compared to the level of MN protein in the healthy tissue is indicative of the presence of an MN-related disorder. 
     
     
         57 . The method according to  claim 52 , wherein the step of detecting is achieved by a nuclear imaging modality. 
     
     
         58 . The method according to  claim 57 , wherein the nuclear imaging modality is SPECT or PET. 
     
     
         59 . A kit comprising the antibody or antibody fragment according to  claim 4 , and a set of instructions for using the kit in a method of treating an MN-related disorder. 
     
     
         60 . A kit comprising the composition according to  claim 20  and a set of instructions for using the kit in a method of treating an MN-related disorder. 
     
     
         61 . A kit comprising the composition according to  claim 33  and a set of instructions for using the kit in a method of treating an MN-related disorder. 
     
     
         62 - 68 . (canceled) 
     
     
         69 . A method of treating an MN-related disorder characterized by an abnormal level of MN in a subject comprising administering a therapeutically effective amount of an antibody or antibody fragment having an antigenic binding site specifically directed against an MN protein, wherein the antigenic binding site comprises a set of CDR sequences
 [3ef2] SEQ ID NOS: 58, 64, 71, 107, 109, and 111;   [1e4] SEQ ID NOS: 59, 65, 72, 107, 109, and 111;   [3a4] SEQ ID NOS: 60, 66, 73, 108, 110, and 112;   [3ab4] SEQ ID NOS: 61, 67, 74, 87, 91, and 95;   [3ah10] SEQ ID NOS: 61, 68, 75, 88, 92, and 96;   [3bb2] SEQ ID NOS: 62, 69, 76, 98, 100, and 102;   [1aa1] SEQ ID NOS: 77, 78, 79, 86, 90, and 94;   [5a6] SEQ ID NOS: 80, 82, 84, 99, 101, and 103; and   [5aa3] SEQ ID NOS: 81, 83, 85, 104, 105, and 106.   
     
     
         70 - 71 . (canceled) 
     
     
         72 . The method according to  claim 69 , wherein the antibody or antibody fragment binds to the MN protein with a dissociation constant of about 0.15 nM to about 50 nM. 
     
     
         73 . The method according to  claim 69 , wherein the antibody is an IgG. 
     
     
         74 . The method according to  claim 69 , wherein the antibody or antibody fragment is an IgG1, IgG2a, IgG2b, IgG3, IgM, IgD, IgE, IgA, or IgM, a Fab fragment, F(ab′) 2  fragment, scFv fragment, Fv fragment, a diabody, linear antibody, single-chain antibody, bispecific antibody, chimeric antibody or multispecific antibody. 
     
     
         75 . The method according to  claim 69 , wherein the antibody or antibody fragment is humanized. 
     
     
         76 . The method according to  claim 69 , wherein the CDR1, CDR2, and CDR3 are non-human. 
     
     
         77 - 80 . (canceled) 
     
     
         81 . The method according to  claim 69 , wherein the antibody or antibody fragment is conjugated to a cytotoxic agent. 
     
     
         82 . The method according to  claim 81 , wherein the cytotoxic agent is selected from the group consisting of: monomethylauristatin-E or functional analog thereof, monomethylauristatin-F or functional analog thereof, aplidin, azaribine, anastrozole, azacytidine, bleomycin, bortezomib, bryostatin-1, busulfan, calicheamycin, camptothecin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatin, irinotecan (CPT-1 1), SN-38, carboplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunomycin glucuronide, daunorubicin, dexamethasone, diethylstilbestrol, doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, ethinyl estradiol, estramustine, etoposide, etoposide glucuronide, etoposide phosphate, floxuridine (FUdR), 3′,5′-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, fluorouracil, fluoxymesterone, gemcitabine, hydroxyprogesterone caproate, hydroxyurea, idarubicin, ifosfamide, L-asparaginase, leucovorin, lomustine, mechlorethamine, medroprogesterone acetate, megestrol acetate, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, phenyl butyrate, prednisone, procarbazine, paclitaxel, pentostatin, PSI-341, semustine streptozocin, tamoxifen, taxanes, taxol, testosterone propionate, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, velcade, vinblastine, vinorelbine, vincristine, ricin, abrin, ribonuclease, onconase, rapLR1, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin,  Pseudomonas exotoxin, Pseudomonas  endotoxin, and combinations thereof. 
     
     
         83 . The method according to  claim 82 , wherein the cytotoxic agent is monomethylauristatin-E or functional analog thereof. 
     
     
         84 . The method according to  claim 69 , further comprising co-administering a-cancer agent. 
     
     
         85 . The method according to  claim 84 , wherein the anti-cancer agent is selected from the group consisting of bleomycin, docetaxel (Taxotere), doxorubicin, edatrexate, erlotinib (Tarceva), etoposide, finasteride (Proscar), flutamide (Eulexin), gemcitabine (Gemzar), genitinib (Irresa), goserelin acetate (Zoladex), granisetron (Kytril), imatinib (Gleevec), irinotecan (Campto/Camptosar), ondansetron (Zofran), paclitaxel (Taxol), pegaspargase (Oncaspar), pilocarpine hydrochloride (Salagen), porfimer sodium (Photofrin), interleukin-2 (Proleukin), rituximab (Rituxan), topotecan (Hycamtin), trastuzumab (Herceptin), Triapine, vincristine, vinorelbine tartrate (Navelbine), and therapeutic antibodies or fragments thereof. 
     
     
         86 . The method according to  claim 84 , wherein the anti-cancer agent is an agent that blocks or inhibits a multi-drug resistance phenotype selected from the group consisting of tamoxifen, verapamil and cyclosporin A. 
     
     
         87 . The method according to  claim 69 , wherein the MN-related disorder is a cancer. 
     
     
         88 . The method according to  claim 87 , wherein the cancer is a solid tumor cancer. 
     
     
         89 . The method according to  claim 88 , wherein the solid tumor is in or originating from the breast, respiratory tract, lung, brain, reproductive organ, digestive tract, colon, urinary tract, kidney, esophagus, cervix, eye, liver, skin, head, neck, thyroid, and parathyroid. 
     
     
         90 . An antibody or antibody fragment having an antigenic binding site specifically directed against an MN protein, wherein the antigenic binding site comprises a pair of heavy chain variable and light chain variable regions
 the heavy chain variable region of SEQ ID NO:133 and the light chain variable region of SEQ ID NO:134;   the heavy chain variable region of SEQ ID NO:135 and the light chain variable region of SEQ ID NO:136;   the heavy chain variable region of SEQ ID NO:137 and the light chain variable region of SEQ ID NO:138;   the heavy chain variable region of SEQ ID NO:139 and the light chain variable region of SEQ ID NO:140;   the heavy chain variable region of SEQ ID NO:141 and the light chain variable region of SEQ ID NO:142;   the heavy chain variable region of SEQ ID NO:143 and the light chain variable region of SEQ ID NO:144;   the heavy chain variable region of SEQ ID NO:147 and the light chain variable region of SEQ ID NO:148;   the heavy chain variable region of SEQ ID NO:149 and the light chain variable region of SEQ ID NO:150; and   the heavy chain variable region of SEQ ID NO:151 and the light chain variable region of SEQ ID NO:152.   
     
     
         91 . An anti-MN IgG antibody encoded by the nucleotide sequence of SEQ ID NO: 153.