Murine, chimeric, humanized or human anti-TNF-alpha antibodies

Abstract

The present invention concerns compositions and methods of use of bispecific antibodies comprising at least one anti-TNF-α antibody or antigen-binding fragment thereof and at least one anti-IL-6 antibody or antigen-binding fragment thereof. Preferably, the bispecific antibody is in the form of a DNL® complex. The anti-TNF-α or anti-IL-6 antibodies may comprise specific CDR sequences disclosed herein. The compositions and methods are of use to treat autoimmune disease, immune system dysfunction or inflammatory disease, as disclosed herein.

What is claimed is: 
     
       1. A murine, chimeric, humanized or human anti-TNF-α antibody or antigen-binding fragment thereof comprising the heavy chain CDR sequences CDR1 (GFWN, SEQ ID NO:113), CDR2 (YISYSGRTYYNPSLKS, SEQ ID NO:114) and CDR3 (DANYVLDY, SEQ ID NO:115) and the light chain CDR sequences CDR1 (KSSQSLLNSSTQKNYLA, SEQ ID NO:116), CDR2 (FASARES, SEQ ID NO:117) and CDR3 (QQHYRTPFT, SEQ ID NO:118). 
     
     
       2. The anti-TNF-α antibody or fragment thereof of  claim 1 , wherein the antibody allotype is selected from the group consisting of nG1m1, G1m3, nG1m1,2 and Km3. 
     
     
       3. The anti-TNF-α antibody or fragment thereof of  claim 1 , wherein the antibody or fragment is a naked antibody or fragment. 
     
     
       4. The anti-TNF-α antibody or fragment thereof of  claim 1 , wherein the antibody is conjugated to an agent selected from the group consisting of a drug, an anti-angiogenic agent, a pro-apoptotic agent, an antibiotic, a hormone, a hormone antagonist, an immunomodulator, a cytokine, a chemokine, a prodrug, and an enzyme. 
     
     
       5. The anti-TNF-α antibody or fragment thereof of  claim 4 , wherein the drug possesses a pharmaceutical property selected from the group consisting of antimitotic, antikinase, anti-tyrosine kinase, alkylating, antimetabolite, antibiotic, alkaloid, anti-angiogenic, pro-apoptotic agent, and immune modulator. 
     
     
       6. The anti-TNF-α antibody or fragment thereof of  claim 4 , wherein the drug is selected from the group consisting of 5-fluorouracil, aplidin, azaribine, anastrozole, anthracyclines, bendamustine, bleomycin, bortezomib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celecoxib, chlorambucil, cisplatinum, Cox-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicine (2P-DOX), pro-2P-DOX, cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, estramustine, epipodophyllotoxin, estrogen receptor binding agents, etoposide (VP16), etoposide glucuronide, etoposide phosphate, floxuridine (FUdR), 3′,5′-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, farnesyl-protein transferase inhibitors, gemcitabine, hydroxyurea, idarubicin, ifosfamide, L-asparaginase, lenolidamide, leucovorin, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, navelbine, nitrosourea, plicomycin, procarbazine, paclitaxel, pentostatin, PSI-341, raloxifene, semustine, streptozocin, tamoxifen, temazolomide, transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vinorelbine, vinblastine, vincristine and vinca alkaloids. 
     
     
       7. The anti-TNF-α antibody or fragment thereof of  claim 4 , wherein the chemokine is selected from the group consisting of RANTES, MCAF, MIP1-alpha, MIP1-Beta and IP-10. 
     
     
       8. The anti-TNF-α antibody or fragment thereof of  claim 4 , wherein the anti-angiogenic agent is selected from the group consisting of angiostatin, baculostatin, canstatin, maspin, anti-VEGF antibody, anti-PlGF peptide, anti-vascular growth factor antibody, anti-Flk-1 antibody, anti-Flt-1 antibody, anti-Kras antibody, anti-cMET antibody, anti-MIF (macrophage migration-inhibitory factor) antibody, laminin peptide, fibronectin peptide, plasminogen activator inhibitor, tissue metalloproteinase inhibitor, interferon, interleukin-12, IP-10, Gro-ß, thrombospondin, 2-methoxyoestradiol, proliferin-related protein, carboxiamidotriazole, CM101, Marimastat, pentosan polysulphate, angiopoietin-2, interferon-alpha, herbimycin A, PNU145156E, 16K prolactin fragment, Linomide (roquinimex), thalidomide, pentoxifylline, genistein, TNP-470, endostatin, paclitaxel, accutin, angiostatin, cidofovir, vincristine, bleomycin, AGM-1470, platelet factor 4 and minocycline. 
     
     
       9. The anti-TNF-α antibody or fragment thereof of  claim 4 , wherein the immunomodulator is selected from the group consisting of a cytokine, a stem cell growth factor, a lymphotoxin, a hematopoietic factor, a colony stimulating factor (CSF), an interferon (IFN), erythropoietin, and thrombopoietin. 
     
     
       10. The anti-TNF-α antibody or fragment thereof of  claim 9 , wherein the cytokine is selected from the group consisting of human growth hormone, N-methionyl human growth hormone, bovine growth hormone, parathyroid hormone, thyroxine, insulin, proinsulin, relaxin, prorelaxin, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), hepatic growth factor, prostaglandin, fibroblast growth factor, prolactin, placental lactogen, OB protein, tumor necrosis factor-α, tumor necrosis factor-ß, mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, integrin, thrombopoietin (TPO), NGF-ß, platelet-growth factor, transforming growth factor-α (TGF-α), TGF-ß, insulin-like growth factor-I, insulin-like growth factor-II, interferon-α, interferon-β, interferon-γ, interferon-λ, macrophage-CSF, interleukin-1 (IL-1), IL-la, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-21, IL-25, LIF, FLT-3, angiostatin, thrombospondin, endostatin, and LT (lymphotoxin).