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(12) Patent Application Publication (10) Pub. No.: US 2010/0210567 A1 Bevec (43) Pub US 2010O2.10567A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0210567 A1 Bevec (43) Pub. Date: Aug. 19, 2010 (54) USE OF ATUFTSINASATHERAPEUTIC Publication Classification AGENT (51) Int. Cl. A638/07 (2006.01) (76) Inventor: Dorian Bevec, Germering (DE) C07K 5/103 (2006.01) A6IP35/00 (2006.01) Correspondence Address: A6IPL/I6 (2006.01) WINSTEAD PC A6IP3L/20 (2006.01) i. 2O1 US (52) U.S. Cl. ........................................... 514/18: 530/330 9 (US) (57) ABSTRACT (21) Appl. No.: 12/677,311 The present invention is directed to the use of the peptide compound Thr-Lys-Pro-Arg-OH as a therapeutic agent for (22) PCT Filed: Sep. 9, 2008 the prophylaxis and/or treatment of cancer, autoimmune dis eases, fibrotic diseases, inflammatory diseases, neurodegen (86). PCT No.: PCT/EP2008/007470 erative diseases, infectious diseases, lung diseases, heart and vascular diseases and metabolic diseases. Moreover the S371 (c)(1), present invention relates to pharmaceutical compositions (2), (4) Date: Mar. 10, 2010 preferably inform of a lyophilisate or liquid buffersolution or artificial mother milk formulation or mother milk substitute (30) Foreign Application Priority Data containing the peptide Thr-Lys-Pro-Arg-OH optionally together with at least one pharmaceutically acceptable car Sep. 11, 2007 (EP) .................................. O7017754.8 rier, cryoprotectant, lyoprotectant, excipient and/or diluent. US 2010/0210567 A1 Aug. 19, 2010 USE OF ATUFTSNASATHERAPEUTIC ment of Hepatitis BVirus infection, diseases caused by Hepa AGENT titis B Virus infection, acute hepatitis, chronic hepatitis, full minant liver failure, liver cirrhosis, cancer associated with Hepatitis B Virus infection. 0001. The present invention is directed to the use of the Cancer, Tumors, Proliferative Diseases, Malignancies and peptide compound Thr-Lys-Pro-Arg-OH (Tuftsin) as a thera their Metastases peutic agent for the prophylaxis and/or treatment of cancer, 0008. The term "cancer as used herein refers also to autoimmune diseases, fibrotic diseases, inflammatory dis tumors, proliferative diseases, malignancies and their eases, neurodegenerative diseases, infectious diseases, lung metastases. Examples for cancer diseases are adenocarci diseases, heart and vascular diseases and metabolic diseases. noma, choroidal melanoma, acute leukemia, acoustic neuri noma, ampullary carcinoma, anal carcinoma, astrocytoma, BACKGROUND OF THE INVENTION basal cell carcinoma, pancreatic cancer, desmoid tumor, blad der cancer, bronchial carcinoma, non-Small cell lung cancer 0002 The identification of a therapeutic compound effec (NSCLC), breast cancer, Burkitt's lymphoma, corpus cancer, tive for the prophylaxis and/or treatment of a disease can be CUP-syndrome (carcinoma of unknown primary), colorectal based on the activity of the compound in a biological assay. A cancer, Small intestine cancer, Small intestinal tumors, ova biological assay that mimics a disease causative mechanism rian cancer, endometrial carcinoma, ependymoma, epithelial can be used to test the therapeutic activity of a candidate cancertypes, Ewing's tumors, gastrointestinal tumors, gastric peptide. cancer, gallbladder cancer, gallbladder carcinomas, uterine 0003. The causative mechanism of many diseases is the cancer, cervical cancer, cervix, glioblastomas, gynecologic over activity of a biological pathway. A peptide that can tumors, ear, nose and throat tumors, hematologic neoplasias, reduce the activity of the biological pathway can be effective hairy cell leukemia, urethral cancer, skin cancer, skin testis in the prophylaxis and/or treatment of the disease caused by cancer, brain tumors (gliomas), brain metastases, testicle can the over activity of the biological pathway. Similarly the cer, hypophysis tumor, carcinoids, Kaposi's sarcoma, laryn causative mechanism of many diseases is the over production geal cancer, germ cell tumor, bone cancer, colorectal carci of a biological molecule. A peptide that can reduce the pro noma, head and neck tumors (tumors of the ear, nose and duction of the biological molecule or block the activity of the throat area), colon carcinoma, craniopharyngiomas, oral can over produced biological molecule can be effective in the cer (cancer in the mouth area and on lips), cancer of the prophylaxis and/or treatment of the disease caused by the central nervous system, liver cancer, liver metastases, leuke over production of the biological molecule. mia, eyelid tumor, lung cancer, lymph node cancer 0004 Conversely, the causative mechanism of many dis (Hodgkin’s/Non-Hodgkin’s), lymphomas, stomach cancer, eases is the under activity of a biological pathway. A peptide malignant melanoma, malignant neoplasia, malignant tumors that can increase the activity of the biological pathway can be gastrointestinal tract, breast carcinoma, rectal cancer, effective in the prophylaxis and/or treatment of the disease medulloblastomas, melanoma, meningiomas, Hodgkin's dis caused by the under activity of the biological pathway. Also ease, mycosis fungoides, nasal cancer, neurinoma, neuroblas similarly the causative mechanism of many diseases is the toma, kidney cancer, renal cell carcinomas, non-Hodgkin’s under production of a biological molecule. A peptide that can lymphomas, oligodendroglioma, esophageal carcinoma, increase the production of the biological molecule or mimic osteolytic carcinomas and osteoplastic carcinomas, osteosa the biological activity of the under produced biological mol rcomas, ovarial carcinoma, pancreatic carcinoma, penile can ecule can be effective in the prophylaxis and/or treatment of cer, plasmocytoma, squamous cell carcinoma of the head and the disease caused by the under production of the biological neck (SCCHN), prostate cancer, pharyngeal cancer, rectal molecule. carcinoma, retinoblastoma, vaginal cancer, thyroid carci 0005. It is the object of the present invention to provide a noma, Schneeberger disease, esophageal cancer, spinalioms, compound for the prophylaxis and/or treatment of cancer, T-cell lymphoma (mycosis fungoides), thymoma, tube carci autoimmune diseases, fibrotic diseases, inflammatory dis noma, eye tumors, urethral cancer, urologic tumors, urothe eases, neurodegenerative diseases, infectious diseases, lung lial carcinoma, Vulva cancer, wart appearance, Soft tissue diseases, heart and vascular diseases and metabolic diseases. tumors, soft tissue sarcoma, Wilm's tumor, cervical carci 0006. The object of the present invention is solved by the noma and tongue cancer. teaching of the independent claims. Further advantageous 0009. The peptide of the present invention was tested features, aspects and details of the invention are evident from using the assays described in Examples 1-7, 9-17 for their the dependent claims, the description, and the examples of the effect as active therapeutic agents in the prophylaxis and/or present application. treatment of cancer, proliferative diseases, tumors and their metaStaSeS. DESCRIPTION OF THE INVENTION Infectious Disease 0007. The present invention relates to the use of the pep tide Thr-Lys-Pro-Arg-OH (Tuftsin), its use as a therapeutic in 0010. The immune system in higher vertebrates represents medicine and for the prophylaxis and/or treatment of cancer, the first line of defense against various antigens that can enter autoimmune diseases, fibrotic diseases, inflammatory dis the vertebrate body, including microorganisms such as bac eases, neurodegenerative diseases, infectious diseases, lung teria, fungi and viruses that are the causative agents of a diseases, heart and vascular diseases and metabolic diseases. variety of diseases. Also disclosed are pharmaceutical formulations preferably in 0011. Despite large immunization programs, viral infec form of a lyophilisate or liquid buffer solution or artificial tions, such as influenza virus, human immunodeficiency virus mother milk formulation containing the inventive peptide. (“HIV), herpes simplex virus (“HSV”, type 1 or 2), human The peptide is especially useful for prophylaxis and/or treat papilloma virus (“HPV, type 16 or 18), human cytomega US 2010/0210567 A1 Aug. 19, 2010 lovirus (“HCMV) or human hepatitis B or C virus (“HBV, Zoster (shingles), HIV Infection, human ehrlichiosis, human Type B; "HCV, type C) infections, remain a serious source parainfluenza virus infection, influenza, isosporiasis (Isos of morbidity and mortality throughout the world and a sig pora infection), Lassa fever, leishmaniasis, Kala-azar (Kala nificant cause of illness and death among people with azar, Leishmania Infection), lice (body lice, head lice, pubic immune-deficiency associated with aging or different clinical lice), Lyme disease, malaria, Marburg hemorrhagic fever, conditions. Although antiviral chemotherapy with com measles, meningitis, mosquito-borne diseases, Mycobacte pounds such as amantadine and rimantadine have been shown rium avium complex (MAC) infection, Naegleria infection, to reduce the duration of symptoms of clinical infections (i.e., nosocomial infections, nonpathogenic intestinal ameobae influenza infection), major side effects and the emergence of drug-resistant variants have been described. New classes of infection, onchocerciasis (river blindness), opisthorciasis antiviral agents designed to target particular viral proteins (Opisthorcis infection), parvovirus infection, plague, Pneu Such as influenza neuraminidase are being developed. How mocystis carinii pneumonia (PCP), polio, Q fever, rabies, ever, the ability of viruses to
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