(19) TZZ¥¥_T (11) EP 3 539 985 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 18.09.2019 Bulletin 2019/38 C07K 16/28 (2006.01) (21) Application number: 19154773.6 (22) Date of filing: 22.02.2013 (84) Designated Contracting States: • STULL, Robert, A. AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Alameda, CA 94501 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • TORGOV, Michael PL PT RO RS SE SI SK SM TR San Franciso, CA 94103 (US) Designated Extension States: • SHAO, Hui BA ME Foster City, CA 94404 (US) •LIU,David (30) Priority: 24.02.2012 US 201261603203 P Pacifica, California 94044 (US) (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: (74) Representative: Wilding, James Roger 13707529.7 / 2 817 339 Mathys & Squire LLP The Shard (71) Applicant: AbbVie Stemcentrx LLC 32 London Bridge Street North Chicago, IL 60064-6400 (US) London SE1 9SG (GB) (72) Inventors: Remarks: • SAUNDERS, Laura •This application was filed on 31-01-2019 as a San Francisco, CA 94107 (US) divisional application to the application mentioned • DYLLA, Scott, J. under INID code 62. Mountain View, CA 94043 (US) •Claims filed after the date of receipt of the divisional • FOORD, Orit application (Rule 68(4) EPC). Foster City, CA 94404 (US) (54) ANTI SEZ6 ANTIBODIES AND METHODS OF USE (57) Novel modulators, including antibodies and derivatives thereof, and methods of using such modulators to treat proliferative disorders are provided. EP 3 539 985 A1 Printed by Jouve, 75001 PARIS (FR) EP 3 539 985 A1 Description CROSS REFERENCED APPLICATIONS 5 [0001] This application claims priority from U. S. Provisional Patent Application Ser. No. 61/603,203 filed on February 24, 2012 which is incorporated herein by reference in its entirety. SEQUENCE LISTING 10 [0002] The instant application contains a sequence listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on February 19, 2013, is named 11200.0014-00304 and is 450,013 bytes in size. FIELD OF THE INVENTION 15 [0003] This application generally relates to novel compounds, compositions and methods of their use in diagnosing, preventing, treating or ameliorating proliferative disorders and any expansion, recurrence, relapse or metastasis thereof. In a broad aspect, the present invention relates to the use of seizure related 6 homolog (SEZ6) modulators, including anti-SEZ6 antibodies and fusion constructs, for the treatment, diagnosis or prophylaxis of neoplastic disorders. Selected 20 embodiments of the present invention provide for the use of such SEZ6 modulators, including antibody drug conjugates, for the immunotherapeutic treatment of malignancies preferably comprising a reduction in tumor initiating cell frequency. BACKGROUND OF THE INVENTION 25 [0004] Stem and progenitor cell differentiation and cell proliferation are normal ongoing processes that act in concert to support tissue growth during organogenesis and cell replacement and repair of most tissues during the lifetime of all living organisms. In the normal course of events cellular differentiation and proliferation is controlled by numerous factors and signals that are generally balanced to maintain cell fate decisions and tissue architecture. Thus, to a large extent it is this controlled microenvironment that regulates cell division and tissue maturation where signals are properly generated 30 based on the needs of the organism. In this regard cell proliferation and differentiation normally occur only as necessary for the replacement of damaged or dying cells or for growth. Unfortunately, disruption of cell proliferation and/or differ- entiation can result from a myriad of factors including, for example, the under- or overabundance of various signaling chemicals, the presence of altered microenvironments, genetic mutations or some combination thereof. When normal cellular proliferation and/or differentiation is disturbed or somehow disrupted it can lead to various diseases or disorders 35 including proliferative disorders such as cancer. [0005] Conventional treatments for cancer include chemotherapy, radiotherapy, surgery, immunotherapy (e.g., bio- logical response modifiers, vaccines or targeted therapeutics) or combinations thereof. Unfortunately, certain cancers are non-responsive or minimally responsive to such treatments. For example, in some patients tumors exhibit gene mutations that render them non-responsive despite the general effectiveness of selected therapies. Moreover, depending 40 on the type of cancer and what form it takes some available treatments, such as surgery, may not be viable alternatives. Limitations inherent in current standard of care therapeutics are particularly evident when attempting to treat patients who have undergone previous treatments and have subsequently relapsed. In such cases the failed therapeutic regimens and resulting patient deterioration may contribute to refractory tumors which often manifest themselves as a relatively aggressive disease that ultimately proves to be incurable. Although there have been great improvements in the diagnosis 45 and treatment of cancer over the years, overall survival rates for many solid tumors have remained largely unchanged due to the failure of existing therapies to prevent relapse, tumor recurrence and metastases. Thus, it remains a challenge to develop more targeted and potent therapies for proliferative disorders. SUMMARY OF THE INVENTION 50 [0006] These and other objectives are provided for by the present invention which, in a broad sense, is directed to methods, compounds, compositions and articles of manufacture that may be used in the treatment of SEZ6 associated disorders (e.g., proliferative disorders or neoplastic disorders). To that end, the present invention provides novel seizure related 6 homolog (or SEZ6) modulators that effectively target tumor cells and/or cancer stem cells and may be used 55 to treat patients suffering from a wide variety of malignancies. As will be discussed in more detail herein, there are at least two naturally occurring SEZ6 isoforms or variants and the disclosed modulators may comprise or associate selec- tively with one isoform or the other or with both. Moreover, in certain embodiments the disclosed SEZ6 modulators may further react with one or more SEZ family members (e.g., SEZ6L or SEZ6L2) or, in other embodiments, may be generated 2 EP 3 539 985 A1 and selected for so as to exclusively associate or react with SEZ6 isoform(s). In any event the modulators may comprise any compound that recognizes, competes, agonizes, antagonizes, interacts, binds or associates with a SEZ6 polypeptide or gene (or fragment thereof) and modulates, adjusts, alters, changes or modifies the impact of the SEZ6 protein on one or more physiological pathways. Thus, in a broad sense the present invention is generally directed to isolated SEZ6 5 modulators and use thereof. In preferred embodiments the invention is more particularly directed to isolated SEZ6 modulators comprising antibodies (i.e., antibodies that immunopreferentially bind, react with or associate with at least one isoform of SEZ6) that, in particularly preferred embodiments, are associated or conjugated to one or more cytotoxic agents.Moreover, as discussed extensivelybelow, such modulators may be used toprovide pharmaceutical compositions useful for the prophylaxis, diagnosis or treatment of proliferative disorders. 10 [0007] In selected embodiments of the invention, SEZ6 modulators may comprise a SEZ6 polypeptide or fragments thereof, either in an isolated form or fused or associated with other moieties (e.g., Fc-SEZ6, PEG-SEZ6 or SEZ6 asso- ciated with a targeting moiety). In other selected embodiments SEZ6 modulators may comprise SEZ6 antagonists which, for the purposes of the instant application, shall be held to mean any construct or compound that recognizes, competes, interacts, binds or associates with SEZ6 and neutralizes, eliminates, reduces, sensitizes, reprograms, inhibits or controls 15 the growth of neoplastic cells including tumor initiating cells. In preferred embodiments the SEZ6 modulators of the instant invention comprise anti-SEZ6 antibodies, or fragments or derivatives thereof, that have unexpectedly been found to silence, neutralize, reduce, decrease, deplete, moderate, diminish, reprogram, eliminate, or otherwise inhibit the ability of tumor initiating cells to propagate, maintain, expand, proliferate or otherwise facilitate the survival, recurrence, regen- eration and/or metastasis of neoplastic cells. In particularly preferred embodiments the antibodies or immunoreactive 20 fragments may be associated with or conjugated to one or more anti-cancer agents (e.g., a cytotoxic agent). [0008] With regard to such modulators it will be appreciated that compatible antibodies may take on any one of a number of forms including, for example, polyclonal and monoclonal antibodies, chimeric, CDR grafted, humanized and human antibodies and immunoreactive fragments and/or variants of each of the foregoing. Preferred embodiments will comprise antibodies that are relatively non-immunogenic such as humanized or fully human constructs. Of course, in 25 view of the instant disclosure those skilled in the art could readily identify one or more complementarity determining regions (CDRs) associated with heavy and light chain variable regions of SEZ6 antibody modulators and use those CDRs to engineer or fabricate chimeric, humanized or CDR grafted