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WO 2013/179143 A2 5 December 2013 (05.12.2013) P O P C T

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WO 2013/179143 A2 5 December 2013 (05.12.2013) 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 2013/179143 A2 5 December 2013 (05.12.2013) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61M 1/36 (2006.01) A61K 38/19 (2006.01) kind of national protection available): AE, AG, AL, AM, C07K 16/28 (2006.01) A61M 1/34 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61P 35/00 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR, PCT/IB2013/001583 KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 3 1 May 2013 (3 1.05.2013) OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (25) Filing Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, PCT/EP20 12/002340 1 June 2012 (01 .06.2012) EP GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 12196527. 1 11 December 2012 ( 11. 12.2012) EP UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (71) Applicant: BIOPHERESIS TECHNOLOGIES, INC. EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, [US/US]; 400 Galleria Parkway, Suite 1950, Atlanta, GA MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 30339 (US). TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: BERG, Sabine; Wiesenstr. 8, 17495 Zussow, OT Nepzin (DE). WIESNER, Peter; Am Zapfenberg 18, Published: 6912 1 Heidelberg (DE). — without international search report and to be republished (74) Agent: OSBORNE, David, W.; Thorpe North and West upon receipt of that report (Rule 48.2(g)) ern, 8180 South 700 East, Suite 350, Sandy, UT 84070- — with sequence listing part of description (Rule 5.2(a)) 0562 (US). < (54) Title: SENSITIZATION OF CANCER CELLS BY THE REMOVAL OF SOLUBLE TUMOR NECROSIS FACTOR RE- CEPTORS (57) Abstract: The present invention relates to a molecule binding to soluble tumor necrosis factor receptor (sTNFR) for use in a method for sensitizing a tumor cell in a patient to a treatment with a chemotherapeutic agent, wherein said molecule is immobilized on a solid support that is contacted with a body fluid of said patient. Furthermore, the present invention refers to a method for sensit- izing a tumor cell and to a body fluid from which sTNFR has been removed for use in a method for sensitizing a tumor cell in a pa tient to a treatment with a chemotherapeutic agent. Moreover, the present invention refers to a chemotherapeutic agent for use in a method for treating a tumor in a patient for sensitizing a tumor cell of said tumor in said patient to a treatment with said chemothera- peutic agent. Sensitization of Cancer Cells by the Removal of Soluble Tumor Necrosis Factor Receptors The present invention relates to a molecule binding to soluble tumor necrosis factor receptor (sTNFR) for use in a method for sensitizing a tumor cell in a patient to a treatment with a chemotherapeutic agent, wherein said molecule is immobilized on a solid support that is contacted with a body fluid of said patient. Furthermore, the present invention refers to a method for sensitizing a tumor cell and to a body fluid from which sTNFR has been removed for use in a method for sensitizing a tumor cell in a patient to a treatment with a chemotherapeutic agent. Moreover, the present invention refers to a chemotherapeutic agent for use in a method for treating a tumor in a patient for sensitizing a tumor cell of said tumor in said patient to a treatment with said chemotherapeutic agent. n the developed countries, cancer is one of the major causes of death throughout the population. Therefore, various therapeutic methods have been developed since decades. However, so far, no therapeutic approach is fully satisfying. Today, cancer therapy is mainly based on chemotherapy, targeted small molecules, radiation therapy, surgery, immunotherapy, monoclonal antibody therapy and/or other methods. Conventional chemotherapeutic cancer therapy is based on the use of comparably high concentrations of agents that have cytotoxic effects predominantly on neoplastic cells. The predominant killing of neoplastic cells occurs due to the fact that cancer cells replicate faster than most other cells of the adult human body. However, it is widely known that due to the high concentrations of chemotherapeutic agents required for effective chemotherapeutic treatments, also other cell types replicating relatively fast, such as, e.g., hair follicle cells and mucosa cells, are severely impaired. Therefore, the patient is exposed to undesired side effects. Adverse effects related to the chemotherapeutic treatment can lead to the premature discontinuation of the therapeutic treatment. In some instances chemotherapy can even cause the death of the patient. Alternatively or additionally, surgery and radiation are used to reduce tumor bulk. Success rates for these therapeutic approaches are limited due to the inoperability of several organs or sites of the human body, insensitivity of organs to radiation, or acquired radioresistance of primary or metastatic tumor lesions. A surgical procedure may even require the amputation of a limb, a breast, a testicle, an inner organ, a part of the skin and/or parts of one or more of the aforementioned. Further, a surgical procedure may lead to an artificial anus and/or to a bladder catheter. Likewise, radiation may lead to severe symptoms of intoxication. Other treatments have been tried in an attempt to improve mortality and morbidity. Today, some types of cancer can be treated by immunotherapy (e.g., therapeutic vaccines such as sipuleucel-T, or cytokine-based immunotherapy (e.g. Interleukin-2, Interferon-alpha)), monoclonal antibody therapy (e.g. bevacizumab), targeted small molecules (e.g., imatinib) and/or other methods, such as, e.g., cryoablation or isolated organ perfusion. These treatments may bear significant advantages in comparison to the conventional chemotherapeutic treatments described above. However, many of these treatments have limited efficacy, are associated with severe toxicities, and/or can only be used for one or few types of cancer. Therefore, there are numerous types of cancer which can, so far, only be treated with conventional cytotoxic agents, or which cannot be treated effectively at all. Irrespective of recent advances there remains a high unmet medical need associated with common malignancies with high mortality, high morbidity, high rates of recurrence, short periods of disease- or progression-free survival, rapid tumor growth, and high risk of formation of (micro-) metastases. The addition of cytokines, alone or in combination, such as, e.g., tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-γ), and interleukin-2 (IL-2) have been used clinically, but have led to durable remissions only in small numbers of patients treated and produced no significant clinical responses in overall target populations. A still further therapeutic strategy is the removal of molecules based on the molecular weight by means of ultrapheresis (therapeutic apheresis, plasmapheresis) promoting an immune attack on the tumors by the patient's own white blood cells (cf, US 4,708,713). In particular, it has been demonstrated that the removal of components present in the blood having a molecular weight of 120,000 Da (dalton) or less can lead to an induction of an immune response against transformed, infected or diseased tissue (cf, US 6,620,382). However, the unspecific removal of a large fraction of components having a molecular weight of 120,000 Da may lead to significant disadvantages as also molecules that have positive effects on the patient's vitality such as, e.g., TNF- , IL-2, or IFN-γ are removed from the high-molecular weight components containing, e.g., antibodies. A patient may also be treated by the selective removal of one or more cytokine receptors, wherein it is intended to provoke and/or stimulate the patient's immune response against the tumor cells. However, today, for a majority of patients, the most promising therapy is still the treatment by means of a chemotherapeutic agent or by means of a combination of several chemotherapeutic agents. In this context, a well-known problem is that the required concentrations of chemotherapeutic agents are so high that considerable undesired side effects inevitably occur the patient severely suffers from. Moreover, during the treatment, many patients become increasingly insensible to the agent and would require increasing amounts thereof to achieve the therapeutic aim up to concentrations that are not tolerable any more. Therefore, there is still a need for improved cancer therapeutic means that allow usage of lower concentrations of chemotherapeutic agents and nevertheless show comparable efficiency of the therapy. Surprisingly, it could be demonstrated that the removal of sTNFR2 alone or together with one or more cytokine receptors sensitizes tumor cells to a treatment with a chemotherapeutic agent allowing the decrease of the required amount of said chemotherapeutic agent. In a first aspect, the present invention refers to a molecule binding to soluble tumor necrosis factor receptor 2 (sTNFR2) for use in a method for sensitizing a tumor cell in a patient to a treatment with a chemotherapeutic agent, wherein said molecule is used to remove sTNFR2 from a body fluid of said patient.
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