Use of tgf-alpha polypeptide or anti-tgf-alpha antibodies for the treatment of diseases and disorders

Abstract

The invention provides a method of treating a disease or disorder in a subject by inducing a TGF alpha immune response or by administering an anti-TGF-alpha antibody or a biologically active fragment thereof. The TGF-alpha immune response is induced using a TGF-alpha polypeptide or biologically active fragment, a vaccine, a genetic construct or a transformed cell, for example.

1 . A composition for administration to a subject to produce an immune response against TGF-alpha comprising a TGF-alpha polypeptide or a biologically active fragment thereof. 
     
     
         2 . The composition of  claim 1 , further comprising a checkpoint inhibitor. 
     
     
         3 . The composition of  claim 1 , wherein the checkpoint inhibitor inhibits PD-1, PD-L1, PD-L2 or CTLA-4. 
     
     
         4 . A composition for administration to a subject to produce an immune response against TGF-alpha comprising a nucleic acid molecule encoding a TGF-alpha polypeptide or a biologically active fragment thereof. 
     
     
         5 . The composition of  claim 4 , wherein the nucleic acid is DNA or RNA. 
     
     
         6 . The composition of  claim 1  or  4 , further comprising an adjuvant. 
     
     
         7 . An isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the CAR comprises a nucleic acid sequence encoding a TGF-alpha protein or biologically active fragment thereof, a transmembrane domain and an intracellular signaling domain. 
     
     
         8 . The nucleic acid molecule of  claim 7 , wherein the transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of the TGF-alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154. 
     
     
         9 . The nucleic acid molecule of  claim 7 , wherein the nucleic acid sequence encoding the TGF-alpha polypeptide or biologically active fragment is connected to the transmembrane domain by a linker or hinge region. 
     
     
         10 . A chimeric antigen receptor (CAR) polypeptide, wherein the CAR comprises a TGF-alpha protein or biologically active fragment thereof, a transmembrane domain and an intracellular signaling domain. 
     
     
         11 . The polypeptide of  claim 10 , wherein the transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of the TGF-alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154. 
     
     
         12 . The polypeptide of  claim 10 , wherein a nucleic acid encoding the TGF-alpha polypeptide or biologically active fragment is connected to the transmembrane domain by a linker or hinge region. 
     
     
         13 . A method of providing anti-tumor immunity in a subject, comprising administering to the subject an immune cell comprising the nucleic acid molecule of any of  claims 7 - 9  or the polypeptide of any of  claims 10 - 12 . 
     
     
         14 . A pharmaceutical composition comprising a TGF-alpha polypeptide or biologically active fragment thereof and a pharmaceutically acceptable carrier. 
     
     
         15 . The composition of  claim 14 , further comprising a checkpoint inhibitor. 
     
     
         16 . The composition of  claim 15 , wherein the checkpoint inhibitor inhibits PD-1, PD-L1, PD-L2 or CTLA-4. 
     
     
         17 . A method of treating a TGF-alpha related disease or disorder in a subject comprising administering to the subject a therapeutically effective amount of a TGF alpha polypeptide or a biologically active fragment thereof. 
     
     
         18 . The method of  claim 17 , wherein the TGF-alpha related disease or disorder is cancer or an immune disorder. 
     
     
         19 . The method of  claim 18 , wherein the cancer is selected from the group consisting of lung, stomach, prostate, colon, abdomen, bone, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head and neck, nervous (central and peripheral), lymphatic system, pelvic, skin, soft tissue, spleen, thoracic, melanoma and urogenital tract. 
     
     
         20 . The method of  claim 19 , wherein the cancer is colon, stomach, lung or head and neck cancer. 
     
     
         21 . The method of  claim 18 , wherein the immune disorder is selected from the group consisting of Rheumatoid arthritis, Systemic lupus erythematosus, Celiac disease, Crohn's disease, Inflammatory bowel disease, Sjogren's syndrome, Polymyalgia rheumatic, Psoriasis, Multiple sclerosis, Ankylosing spondylitis, Type 1 diabetes, Alopecia areata, Vasculitis, Temporal arteritis, Graves' disease and Hashimoto's thyroiditis. 
     
     
         22 . The method of  claim 17 , wherein the TGF-alpha polypeptide or biologically active fragment thereof has at least 75% identity to the amino acid sequence of any of SEQ ID NOs: 5-8 or 10. 
     
     
         23 . The method of  claim 17 , wherein the TGF-alpha polypeptide or biologically active fragment thereof is a fusion protein. 
     
     
         24 . The method of  claim 17 , wherein the TGF-alpha polypeptide or biologically active fragment thereof is genetically modified. 
     
     
         25 . The method of  claim 17 , wherein the TGF-alpha polypeptide or biologically active fragment thereof comprises a heterologous sequence. 
     
     
         26 . The method of  claim 17 , further comprising administering to the subject a chemotherapeutic agent, radiation and/or an immune modulator either prior to, simultaneously with or following treatment with the TGF-alpha polypeptide or biologically active fragment thereof. 
     
     
         27 . The method of  claim 26 , wherein the chemotherapeutic agent is selected from the group consisting of Actinomycin, Azacitidine, Azathioprine, Bleomycin, Bortezomib, Carboplatin, Capecitabine, Cisplatin, Chlorambucil, Cyclophosphamide, Cytarabine, Daunorubicin, Docetaxel, Doxifluridine, Doxorubicin, Epirubicin, Epothilone, Etoposide, Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Imatinib, Irinotecan, Mechlorethamine, Mercaptopurine, Methotrexate, Mitoxantrone, Oxaliplatin, Paclitaxel, Pemetrexed, Teniposide, Tioguanine, Topotecan, Valrubicin, Vinblastine, Vincristine, Vindesine, Vinorelbine, panitumamab, Erbitux, matuzumab, IMC-IIF 8, TheraCIM hR3, denosumab, Avastin, Humira, Herceptin, Remicade, rituximab, Synagis, Mylotarg, Raptiva, Tysabri, Zenapax, NeutroSpec, tocilizumab, ProstaScint, Bexxar, Zevalin, Xolair, MabThera, ReoPro, MabCampath, Simulect, LeukoScan, CEA-Scan (Verluma, Panorex, alemtuzumab, CDP 870, natalizumab, MGA271, lirilumab, BMS-986016, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and iplimumab. 
     
     
         28 . The method of  claim 27 , wherein the chemotherapeutic agent is pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and/or iplimumab. 
     
     
         29 . The method of  claim 26 , wherein the immune modulator is selected from the group consisting of tocilizumab, CDP870, enteracept, adalimumab, Kineret, abatacept, infliximab, rituzimab, golimumab, Avonex, Rebif, ReciGen, Plegridy, Betaseron, Copaxone, Novatrone, natalizumab, fingolimod, teriflunomide, BG12, Tecfidera, and alemtuzumab. 
     
     
         30 . The method of  claim 17 , further comprising the administration of a checkpoint inhibitor. 
     
     
         31 . The method of  claim 30 , wherein the checkpoint inhibitor inhibits PD-1, PD-L1, PD-L2 or CTLA-4. 
     
     
         32 . The method of  claim 18 , wherein the cancer is a tumor. 
     
     
         33 . The method of  claim 32 , wherein the tumor is resected prior to treatment. 
     
     
         34 . The method of  claim 17 , wherein the subject is a human. 
     
     
         35 . The method of  claim 17 , wherein the administration of the TGF-alpha polypeptide or biologically active fragment thereof induces the in vivo production of anti-TGF-alpha antibodies. 
     
     
         36 . The method of  claim 17 , wherein the TGF-alpha polypeptide or biologically active fragment thereof is administered by intravenous, oral, intramuscular, subcutaneous, intrathecal, infusion, transdermal, sublingual, buccal, rectal, vagina, ocular, optic, nasal, inhalation, nebulization, cutaneous, intraperitoneal or intratumoral administration. 
     
     
         37 . A method of treating a TGF-alpha related disease or disorder in a subject comprising inducing the in vivo production of anti-TGF-alpha antibodies in the subject. 
     
     
         38 . The method of  claim 37 , comprising the administration of a TGF-alpha polypeptide or a biologically active fragment thereof. 
     
     
         39 . The method of  claim 38 , wherein the TGF-alpha polypeptide has at least 75% sequence identity to the amino acid sequence of any of SEQ ID NOs: 5-8 or 10. 
     
     
         40 . The method of  claim 38 , wherein the TGF-alpha polypeptide or a biologically active fragment thereof is a fusion protein. 
     
     
         41 . The method of  claim 38 , wherein the TGF-alpha polypeptide or a biologically active fragment thereof is genetically modified or comprises a heterologous sequence. 
     
     
         42 . The method of  claim 37 , comprising the administration of a TGF-alpha vaccine. 
     
     
         43 . The method of  claim 42 , wherein the vaccine is a DNA, RNA or peptide vaccine. 
     
     
         44 . The method of  claim 37 , comprising administering a cell transformed with a nucleic acid molecule encoding a TGF-alpha polypeptide or a biologically active fragment thereof. 
     
     
         45 . The method of  claim 44 , wherein the cell is transformed with a nucleic acid sequence having at least 75% sequence identity to of any of SEQ ID NOs: 1-4 or 9. 
     
     
         46 . The method of  claim 37 , wherein the TGF-alpha related disease or disorder is cancer or an immune disorder. 
     
     
         47 . The method  claim 37  further comprising administering to the subject a chemotherapeutic agent, radiation or an immune modulator either prior to, simultaneously with or following treatment with the TGF-alpha polypeptide or biologically active fragment thereof, TGF-alpha vaccine or transformed cell. 
     
     
         48 . The method of  claim 47 , wherein the chemotherapeutic agent is pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and/or iplimumab. 
     
     
         49 . The method of  claim 47 , wherein the immune modulator is selected from the group consisting of tocilizumab, CDP870, enteracept, adalimumab, Kineret, abatacept, infliximab, rituzimab, golimumab, Avonex, Rebif, ReciGen, Plegridy, Betaseron, Copaxone, Novatrone, natalizumab, fingolimod, teriflunomide, BG12, Tecfidera, and alemtuzumab. 
     
     
         50 . The method of  claim 37 , further comprising the administration of a checkpoint inhibitor. 
     
     
         51 . The method of  claim 50 , wherein the checkpoint inhibitor inhibits PD-1, PD-L1, PD-L2 or CTLA-4. 
     
     
         52 . A method of treating a TGF-alpha related disease or disorder in a subject comprising administering to the subject a therapeutically effective amount of an anti-TGF-alpha antibody or a biologically active fragment thereof. 
     
     
         53 . The method of  claim 52 , wherein the TGF-alpha related disease or disorder is a TGF-alpha-producing tumor. 
     
     
         54 . The method of  claim 52 , further comprising administering to the subject a chemotherapeutic agent, radiation and/or an immune modulator either prior to, simultaneously with or following treatment with the anti-TGF-alpha antibody or biologically active fragment thereof. 
     
     
         55 . The method of  claim 52 , further comprising the administration of a checkpoint inhibitor. 
     
     
         56 . The method of  claim 55 , wherein the checkpoint inhibitor inhibits PD-1, PD-L1, PD-L2, CTLA-4 or CD137. 
     
     
         57 . The method of  claim 52 , wherein the therapeutically effective amount of an anti-TGF-alpha antibody or a biologically active fragment thereof is sufficient to induce a T cell activation. 
     
     
         58 . The method of  claim 56 , comprising administering a TGF-alpha antibody in combination with an anti-PD1 antibody. 
     
     
         59 . The method of  claim 58 , further comprising administering an anti-CTLA4 antibody. 
     
     
         60 . The method of  claim 52 , wherein the therapeutically effective amount of anti-TGF-alpha antibody is from about 50-1000 μg/injection. 
     
     
         61 . The method of  claim 52 , wherein the therapeutically effective amount of antibody is from about 250-500 μg/injection. 
     
     
         62 . The method of  claim 61 , wherein the injection is from 1-3 times per week. 
     
     
         63 . A method of inducing T cell activation in a subject comprising administering to said subject a therapeutically effective amount of an anti-TGF-alpha antibody or a biologically active fragment thereof. 
     
     
         64 . The method of  claim 58 , wherein the subject has a TGF-alpha producing tumor. 
     
     
         65 . A method of treating cancer in a subject comprising:
 identifying a TGF-alpha-producing tumor from a biological sample from the subject, and   administering to the subject a therapeutically effective amount of an anti-TGF-alpha antibody or a biologically active fragment thereof.   
     
     
         66 . The method of  claim 60 , further comprising the administration of a checkpoint inhibitor. 
     
     
         67 . The method of  claim 55 , wherein the checkpoint inhibitor inhibits PD-1, PD-L1, PD-L2, CTLA-4 or CD137. 
     
     
         68 . The method of  claim 67 , comprising administering a TGF-alpha antibody in combination with an anti-PD1 antibody. 
     
     
         69 . The method of  claim 68 , further comprising administering an anti-CTLA4 antibody. 
     
     
         70 . The method of  claim 65 , wherein the therapeutically effective amount of anti-TGF-alpha antibody is from about 50-1000 μg/injection. 
     
     
         71 . The method of  claim 65 , wherein the therapeutically effective amount of antibody is from about 250-500 μg/injection. 
     
     
         72 . The method of  claim 71 , wherein the injection is from 1-3 times per week. 
     
     
         73 . The method of any of  claim 53 ,  64 , or  65 , wherein the cancer or the tumor is selected from the group consisting of a cancer or tumor of the lung, stomach, prostate, colon, abdomen, bone, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head and neck, nervous (central and peripheral), lymphatic system, pelvic, skin, soft tissue, spleen, thoracic, melanoma and urogenital tract. 
     
     
         74 . The method of  claim 73 , wherein the cancer is colon, stomach, lung breast, melanoma or head and neck cancer.