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(12) United States Patent (10) Patent No.: US 8,580,267 B2 Pedretti Et Al

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(12) United States Patent (10) Patent No.: US 8,580,267 B2 Pedretti Et Al US008580267B2 (12) United States Patent (10) Patent No.: US 8,580,267 B2 Pedretti et al. (45) Date of Patent: Nov. 12, 2013 (54) IMMUNOCYTOKINES FORTUMOUR (56) References Cited THERAPY WITH CHEMOTHERAPEUTIC AGENTS FOREIGN PATENT DOCUMENTS (75) Inventors: Marta Pedretti, Zurich (CH): Dario WO O2/O59264 8, 2002 WO O3,O93478 11, 2003 Neri, Buchs (CH) WO 2004/OO2528 1, 2004 WO 2006/026020 3, 2006 (73) Assignee: Philogen S.p.A., Siena (IT) WO 2006/050834 5, 2006 WO 2007/128563 11, 2007 (*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. Paul, William, Fundamental Immunology, 3rd Edition, Raven Press, New York, 1993, pp. 292-295.* (21) Appl. No.: 13/139,655 Vajdos et al., Comprehensive functional maps of the antigen-binding site of an anti-ErbB2 antibody obtained with shotgun scanning 1-1. mutagenesis. J. Mol. Biol. 320:415-428, 2002.* (22) PCT Filed: Dec. 14, 2009 Bartolomei, M., et al. “Combined treatment of glioblastomapatients with locoregional pre-targeted 90Y-biotin radioimmunotherapy and (86). PCT No.: PCT/EP2009/008920 temozolomide.” QJNuclMed Mol Imaging. Sep. 2004:48(3):220-8. S371 (c)(1) Marlind, J., et al. "Antibody-mediated delivery of interleukin-2 to the (2), (4) Date. Jun. 14, 2011 Stroma of breast cancer strongly enhances the potency of chemo s 9 therapy” Clin Cancer Res. Oct. 15, 2008;14(20):6515-24. Brack, S.S., et al. “Tumor-targeting properties of novel antibodies (87) PCT Pub. No.: WO2010/078916 specific to the large isoform oftenascin-C.” Clin Cancer Res. May 15, PCT Pub. Date: Jul. 15, 2010 2006; 12(10):3200-8. Leins, A., et al. “Expression of tenascin-C in various human brain O O tumors and its relevance for Survival in patients with astrocytoma.” (65) Prior Publication Data Cancer. Dec. 1, 2003:98(11):2430-9. US 2011 FO25O17OA1 Oct. 13, 2011 Ebbinghaus, C., et al. “Engineered vascular-targeting antibody-inter feron-gamma fusion protein for cancer therapy.” IntJ Cancer. Aug. 20, 2005; 116(2):304-13. Related U.S. Application Data * cited by examiner (60) Provisional application No. 61/139,484, filed on Dec. Primary Examiner — Ruixiang Li 19, 2008. (74) Attorney, Agent, or Firm — Dann, Dorfman, Herrell & Skillman; Kathleen D. Rigaut (51) Int. Cl. A 6LX39/395 (2006.01) (57) ABSTRACT A6 IK38/20 (2006.01) Immunocytokine comprising cytokine, e.g. interleukin 2 (IL AOIN 43/73 (2006.01) 2), conjugated to antibody against tumour neovasculature (52) U.S. Cl. antigen, e.g. tenascin-C, for use in combination therapy with USPC ........................ 424/1781; 424/85.2, 514/183 chemotherapeutic agent such as temozolomide. Use of immunocytokine and chemotherapy for treatment of tumours (58) Field of Classification Search e.g. glioblastoma and other cancers. None See application file for complete search history. 12 Claims, 6 Drawing Sheets U.S. Patent Nov. 12, 2013 Sheet 1 of 6 US 8,580,267 B2 r/vryvywryyyyyrry, A WVAAAA/UV/J domains subject to alternative splicing damameramnaanamomb W/AWJVAJAVAJV? s N-S ? EGF like Fibronectin type I like repeats domains Figure 1 U.S. Patent Nov. 12, 2013 Sheet 2 of 6 US 8,580,267 B2 tumor liver lung spleen heart kidney intestine blood Organs Figure 2 U.S. Patent Nov. 12, 2013 Sheet 3 of 6 US 8,580,267 B2 2500 as a F6-2--TMZ 2OOO arA-F6-2 -- TMZ s so e CTRL 10%DMSO tumor 1500 volume (mm) 1000 500 12 A A A A. A days after tumor implantation Figure 3 U.S. Patent Nov. 12, 2013 Sheet 4 of 6 US 8,580,267 B2 1OO m 80 ak-e TMZ E.60 d as Stage.cgregaga>e --TMZ F16 s - e 40 H.kara ages F16-L2 ape CTRL 10% DMSO 10 O dke-eeeeeeeeeeeeeeeeee-eeeeee 10:301 11 ft 50 70 90 110 THERAPY days after tumor implantation Figure 4 U.S. Patent Nov. 12, 2013 Sheet 5 of 6 US 8,580,267 B2 thR$: (NYATI : l ...net days after tumor implantation U.S. Patent Nov. 12, 2013 Sheet 6 of 6 US 8,580,267 B2 a. Maa awa, was a wa Asa was A. Akas. As Kaas Aaa and aaa.. aka is a was as Aa. Adua aal as a has aa kak aa al- alias a RYGMSWRQAPGKGLEWVSAISGSGGST YYADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCAKAHNAFDYWGQGTLVTVSR - - - - - - ------------ee- or- - - - - - - - - - - - - - - - - - see -s a SSELTQDPAWSWALGOTWRITCOGDSLRSYYAS i WYQQKPGQAPWLWIYGKNNRPSGIPDRFSGSSscNASTreacAEDEADYdrissiNipp " VLCF16) : WFGGGTKLTVL wo, rv me -er rvin -rr war err w re rer EFSSSSG SSSSG Linker SSSSG APTssSTKKTQQLEHLLLDLQMILNGINNY--- KNPKLTRMLTFKFYMPKKATELKHLQCLEE ELKPLEEWLNLAQSKNFHLRPRDLISNINVI - IL2 WLELKGSETTFMCEYADETATIVEFLNRWIT FCQSIISTLT Figure 6 US 8,580,267 B2 1. 2 MMUNOCYTOKINES FORTUMIOUR F16 and F16-IL2 have been shown to intensely stain THERAPY WITH CHEMOTHERAPEUTIC aggressive cancer types and to preferentially accumulate at AGENTS the tumour site following intravenous administration 22, 25. Following observation of its excellent safety profile observed This is a national stage application of PCT/EP2009/ 5 in cynomolgus monkeys, F16-IL2 is currently being studied 008920 filed on Dec. 14, 2009 which claims priority to U.S. in two phase Ib clinical trials in combination with doxorubi Provisional patent application No. 61/139,484, filed on Dec. cin or with paclitaxel in patients with metastatic cancer. 19, 2008. The entire disclosure of each of the foregoing Central nervous system tumours rank first among neopla applications is incorporated by reference herein. sia types for the average years of life lost 26. Approximately This invention relates to the treatment of tumours and 10 cancer using a combination of chemotherapeutic agents and 13,000 deaths and 18,000 new cases of central nervous sys immunocytokines. tem tumours occur annually in the US 27. Mortality rates Conventional cytotoxic therapies of cancer often do not are generally similar to incidence rates in most geographical discriminate between tumour and normal tissues. To achieve areas 28. therapeutically relevant concentrations in the tumour mass, 15 The standard of care for patients with glioblastoma large drug doses have to be administered to the patient, lead includes Surgery, radiotherapy and/or temozolomide-based ing to a poor therapeutic index and unacceptable toxicities to pharmacotherapy. Nevertheless, the prognosis of glioblas healthy tissues 1. The selective delivery of therapeutic toma continues to be dismal, in spite of progress made in the agents to the tumour site using antibodies directed against molecular characterisation of the most frequent genetic alter tumour-associated antigens is a strategy to overcome the dis ations found in this disease. advantages of conventional cancer therapies 2, 3, 4. Anti Microvascular proliferation is a characteristic feature of gens that are expressed around the tumour neovasculature are glioblastoma 35. A striking over-expression of the EDB especially attractive targets for antibody-based pharmacode domain of fibronectin in high-grade astrocytomas has been livery applications due to their inherent accessibility for unequivocally established 29:30 and the monoclonal anti blood-borne agents and to the fact that angiogenesis is a 25 body L19 has been shown to target glioblastoma in patients characteristic feature of virtually all aggressive solid tumours 31. Furthermore, radiolabelled preparations of monoclonal 5, 6, 7. antibodies specific to the A1 or to the D domain oftenascin-C Tenascin-C is a large hexameric glycoprotein of the extra have been investigated for the radioimmunotherapy of cellular matrix which modulates cellular adhesion. It is patients with glioblastoma 32. involved in processes such as cell proliferation and cell 30 Bartolomei et al. 33 described treatment of glioblastoma migration and is associated with changes in tissue architec patients with radioimmunotherapy, using biotinylated anti ture as occurring during morphogenesis and embryogenesis tenascin murine monoclonal antibody, avidin and 'Y-biotin, as well as under tumourigenesis orangiogenesis. in combination with temozolomide. Overall survival and pro A strong over-expression of the large isoform of tenascin-C gression free Survival of patients receiving the combined has been reported for a number of tumours, and monoclonal 35 treatment were observed to be higher compared with patients antibodies specific for domains A1 and D, respectively, have who received radioimmunotherapy without temozolomide. been extensively characterised in the clinic 8, 9, 10, 11, 12. The inventors have observed that the combination of an Human monoclonal antibody fragments specific to tenas alkylating agent with an antibody-IL2 conjugate targeted to a cin-C are described in WO2006/050834 and shown to bind tumour-associated antigen of the tumour neovasculature preferentially to tumour tissue relative to normal tissue. These 40 exhibited more effective therapeutic action against the antibodies are useful, for example, in delivering toxins. Such tumour compared with the use of the alkylating agent or the as cytokines, specifically to tumour cells. conjugate alone. Delivery of bioactive agents to the subendothelial extracel F16-IL2 is shown herein to potentiate the therapeutic lular matrix has been demonstrated using derivatives of action of the alkylating agent temozolomide in mice models monoclonal antibodies specific to splice isoforms of 45 of human glioblastoma. A synergistic effect was observed for fibronectin or of tenascin-C 5, 13, 14, 15, 16, 17, 18, 19, 20. the combination of temozolomide and F16-IL2, which pro In particular, promising results obtained with derivatives of duced an anti-tumour effect much greater than would have the human monoclonal antibodies L19 (specific to the alter been expected based on the effects of F16-IL2 or temozolo natively spliced ED-B domain of fibronectin) and F16 (spe mide alone. Subcutaneous U87 glioblastomas were com cific to the extra-domain A1 of tenascin-C) have led to the 50 pletely eradicated in nude mice using the combination treat clinical development of five immunocytokines and radioim ment, compared with only a minor retardation of tumour munoconjugates, based on these antibodies 7, 13, 14, 15, 16.
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