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WO 2015/108719 Al 23 July 2015 (23.07.2015) P O P C T

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WO 2015/108719 Al 23 July 2015 (23.07.2015) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/108719 Al 23 July 2015 (23.07.2015) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, C07K 16/30 (2006.01) A61P 35/00 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/US2015/010219 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 6 January 2015 (06.01 .2015) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 61/927,330 14 January 2014 (14.01.2014) US TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: THE MEDICAL COLLEGE OF WISCON¬ DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, SIN, INC. [US/US]; 8701 Watertown Plank Road, Mil LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, waukee, WI 53226 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventor: JAMES, Michael, A.; S99W24200 Forest Home Avenue, Big Bend, WI 53103 (US). Published: (74) Agent: LEWIS, Jessica; QUARLES & BRADY LLP, 33 — with international search report (Art. 21(3)) East Main St., Suite 900, Madison, WI 53701-21 13 (US). — with amended claims (Art. 19(1)) (81) Designated States (unless otherwise indicated, for every — with sequence listing part of description (Rule 5.2(a)) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (54) Title: TARGETING CLPTMl L FOR TREATMENT AND PREVENTION OF CANCER < o00 (57) Abstract: Provided herein are therapeutic agents having specificity for human CLPTMl L polypeptide, including therapeutic © agents comprising one or more CLPTMl L-targeting agents, compositions comprising such therapeutic agents, and methods of using such compositions for treating or preventing a cancer, pre-cancerous lesion, or other disease condition associated with CLPTMl L protein dysfunction (e.g., pathogenic production, modification, or function). TARGETING CLPT L FOR TREATMENT AND PREVENTION OF CANCER CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Patent Application No. 61/927,330, filed January 14, 2014; which is incorporated herein by reference as if set forth in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH [0002] This invention was made with government support under Grant No. U19 CA128147 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION [0003] The present invention generally relates to compounds and compositions for targeting CLPTM1L polypeptides and methods for using such compounds and compositions to treat or prevent a cancer or other condition associated with CLPTM1L protein dysfunction (e.g., pathogenic production, modification, or function). In particular, the present invention relates to therapeutic agents comprising CLPTM1L targeting moieties and to methods of administering such therapeutic agents to a subject to treat or prevent a disease or condition associated with CLPTM1L protein dysfunction such as non-small cell lung cancer. Therapeutic agents, pharmaceutical compositions, and methods are provided herein. BACKGROUND [0004] Cancer is a disease that begins with mutation of oncogenes and tumor suppressor genes. Mutation of these critical genes allows for a cancer cell to evolve and ultimately results in pathogenic replication (a loss of normal regulatory control leading to excessive cell proliferation) of various given types of cells found in the human body. Tumor formation, tumor survival, and cancer metastasis require anchorage-independent growth and protection from genotoxin- induced apoptosis and anoikis, a programmed cell death mechanism associated with detachment of tumor cells from an extracellular substrate. Tumor cells require protection from apoptosis and anoikis to invade surrounding tissue and to undergo metastasis. [0005] There remains a need in the art for methods for treating or preventing cancer and, in particular, for methods which slow or curb tumor growth and prevent metastasis. BRIEF SUMMARY OF THE INVENTION [0006] In a first aspect, the present invention provides a compound comprising a CLPTM1 L- targeting agent selected from the group consisting of an antibody, a peptide, an aptamer, or a fragment thereof. The CLPTMlL-targeting agent can be a monoclonal antibody specific for at least a portion of a CLPTM1L polypeptide. The CLPTM1L polypeptide can have the amino acid sequence set forth in SEQ ID NO: 2 or a portion thereof. The monoclonal antibody can be specific to peptide having an amino acid sequence selected from the group consisting of SEQ ID NO:4-25. The monoclonal antibody can be a monoclonal anti-CLPTM1L clone selected from the group consisting of 6- , 6-2, 0- , 10-2, and 10-3. The monoclonal antibody can be specific to a CLPTM1L polypeptide having one or more of the mutations set forth in Table 2 . In some cases, the CLPTMlL-targeting agent is a peptide having an amino acid sequence selected from the group consisting of SEQ ID NO:4-25. [0007] In another aspect, the present invention provides a pharmaceutical composition comprising a compound provided herein and a pharmaceutically acceptable carrier. [0008] In yet another aspect, provided herein is an agent according to a compound or composition provided herein for use as a medicament. Further provided is use of such an agent in the manufacture of a medicament. [0009] In a further aspect, provided herein is an article of manufacture comprising a pharmaceutical composition of the invention and instructions for administration to a human subject. [0010] In another aspect, provided herein is a method for treating or preventing a tumor pre- in a subject. The method typically comprises administering a therapeutically effective amount of a compound comprising a CLPTMlL-targeting agent to a subject in need thereof, whereby the tumor is treated or prevented in the subject. In some cases, the CLPTMlL-targeting agent is selected from the group consisting of an antibody, a peptide, and aptamer, or a fragment thereof. The CLPTMlL-targeting agent can be a monoclonal antibody specific for at least a portion of a CLPTM1L polypeptide. The CLPTM1L polypeptide can have the amino acid sequence set forth in SEQ ID NO:2 or a portion thereof. The monoclonal antibody can be specific to a peptide having an amino acid sequence selected from the group consisting of SEQ ID NO:4-25. The monoclonal antibody can be specific to a CLPTM1L polypeptide having one or more of the mutations set forth in Table 2 . The CLPTMlL-targeting agent can be a peptide having an amino acid sequence selected from the group consisting of SEQ ID NO.4-25. [001 1] In some cases, the tumor is a solid tumor selected from the group consisting of glioblastoma, sarcoma, carcinoma, and lymphoma. In some cases, the tumor is associated with a cancer or pre-neoplastic lesion selected from the group consisting of lung cancer, pancreatic cancer, prostate cancer, skin cancer, bladder cancer, kidney cancer, ovarian cancer, colon cancer, colorectal cancer, breast cancer, cervical cancer, brain cancer, esophageal cancer, and stomach cancer, or a pre-neoplastic lesion thereof. The tumor can be associated with lung cancer or a pre-neoplastic lesion thereof. The tumor can exhibit resistance to a chemotherapeutic agent. The chemotherapeutic agent can be selected from the group consisting of cisplatin and gemcitabine. In some cases, the compound is administered with a pharmaceutically acceptable carrier. [001 2] In yet another aspect, provided herein is a method of treating or preventing a disease or condition associated with over-expression or inappropriate expression of a nucleic acid sequence encoding CLPT L in a subject. The method typically comprises administering a compound comprising a CLPT L-targeting agent to a cell, tissue, or organ of a subject at risk of, diagnosed as having, or exhibiting a symptom of the disease or condition. The disease or condition can be a cancer, tumor, (e.g. , solid tumor) or a pre-neoplastic lesion. The tumor, cancer, or pre-neoplastic lesion can be selected from the group consisting of lung cancer, pancreatic cancer, glioblastoma, prostate cancer, skin cancer, bladder cancer, kidney cancer, ovarian cancer, colon cancer, colorectal cancer, breast cancer, cervical cancer, brain cancer, esophageal cancer, stomach cancer, lymphoma, chronic leukemia, and acute leukemia. The tumor can exhibit resistance to a chemotherapeutic agent. The chemotherapeutic agent can be selected from the group consisting of cisplatin and gemcitabine. The CLPTM L-targeting agent can be selected from the group consisting of an antibody, a peptide, and aptamer, or a fragment thereof. The CLPTMI L-targeting agent can be a monoclonal antibody specific for at least a portion of a CLPTM1 L polypeptide. The CLPTM L polypeptide can have the amino acid sequence set forth in SEQ D NO: 2 or a portion thereof. In some cases, the monoclonal antibody is specific to a peptide having an amino acid sequence selected from the group consisting of SEQ ID NO:4-25.
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