Monospecific and multispecific antibodies and method of use

Abstract

This invention relates to monospecific and multispecific antibodies that may be utilized for the diagnosis and treatment of various diseases. In addition, these antibodies may be modified by protease cleavage. Protease control or regulation may be provided by a protease site located in, for example, a linker. These protease-regulated antibodies may also be utilized for the diagnosis and treatment of various diseases.

1 - 28 . (canceled) 
     
     
         29 . A protease regulated antibody comprising a protease cleavage site in a linker located between a variable domain and an N-terminal non-functional antibody domain,
 wherein the protease regulated antibody can only bind an antigen following protease activation that allows removal of the N-terminal non-functional antibody domain.   
     
     
         30 . The antibody of  claim 29 , wherein the antibody is of the Fab-like or IgG-like type. 
     
     
         31 . The antibody of  claim 29 , wherein the protease cleavage sites are selected from the group consisting of SEQ ID NO: 1-32. 
     
     
         32 . The antibody of  claims 29 , wherein said antibody is conjugated to a therapeutic or cytotoxic agent. 
     
     
         33 . The antibody of  claim 32 , wherein said antibody is conjugated to an agent selected from the group consisting of monomethylauristatin-E (MMAE), aplidin, azaribine, anastrozole, azacytidine, bleomycin, bortezomib, bryostatin-1, busulfan, calicheamycin, camptothecin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatin, irinotecan (CPT-Il), 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, ribomiclease, onconase, rapLR1, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin,  Pseudomonas  exotoxin, and  Pseudomonas  endotoxin. 
     
     
         34 . A pharmaceutical composition comprising a therapeutically effective amount of an antibody of any of  claims 29 , in combination with a pharmaceutically acceptable carrier. 
     
     
         35 . A pharmaceutical composition according to  claim 34  in combination with one or more pharmaceutical agents. 
     
     
         36 . Use of an antibody according to  claims 29  in the manufacture of a medicament for the treatment of a disease selected from the group of diseases consisting of cancer, infectious diseases, and autoimmune diseases. 
     
     
         37 . A medicament comprising an antibody of  claim 29 . 
     
     
         38 . A medicament for the treatment of cancer, infectious diseases, and autoimmune diseases comprising an antibody of  claim 29 . 
     
     
         39 . A kit comprising an antibody of  claim 29 . 
     
     
         40 . The kit of  claim 39 , further comprising one or more selected from the group consisting of
 solutions for suspending or fixing the cells,   detectable labels,   solutions for rendering a polypeptide susceptible to the binding of an antibody,   solutions for lysing cells, and   solutions for the purification of polypeptides.