(19) TZZ Z T (11) EP 2 260 858 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 15.12.2010 Bulletin 2010/50 A61K 38/06 (2006.01) A61K 39/395 (2006.01) C07K 16/46 (2006.01) C07K 7/02 (2006.01) (2006.01) (21) Application number: 10175437.2 A61K 47/48 (22) Date of filing: 05.11.2004 (84) Designated Contracting States: • Toki, Brian E. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Shoreline, WA 98155 (US) HU IE IS IT LI LU MC NL PL PT RO SE SI SK TR • Ebens, Allen J. Designated Extension States: San Carlos, CA 94070 (US) AL HR LT LV MK YU • Kline, Toni Beth Seattle, WA 98119 (US) (30) Priority: 06.11.2003 US 518534 P • Polakis, Paul 26.03.2004 US 557116 P Burlingame, CA 94010 (US) 04.08.2004 US 598899 P • Sliwkowski, Mark X. 27.10.2004 US 622455 P San Carlos, CA 94070 (US) • Spencer, Susan D. (62) Document number(s) of the earlier application(s) in Tiburon, CA 94920 (US) accordance with Art. 76 EPC: 04821486.0 / 1 725 249 (74) Representative: Wytenburg, Wilhelmus Johannes et al (71) Applicant: Seattle Genetics, Inc. Mewburn Ellis LLP Bothell, WA 98021 (US) 33 Gutter Lane London (72) Inventors: EC2V 8AS (GB) • Doronina, Svetlana O. Snohomish, WA 98296 (US) Remarks: • Senter, Peter D. This application was filed on 06-09-2010 as a Seattle, WA 98115 (US) divisional application to the application mentioned under INID code 62. (54) Monomethylvaline compounds capable of conjugation to ligands (57) Auristatin peptides, including MeVal-Val-Dil- various linkers, including maleimidocaproyl-val-cit-PAB. Dap-Norephedrine (MMAE) and MeVal-Val-Dil-Dap-Phe The resulting ligand drug conjugates were active in vitro (MMAF), were prepared and attached to Ligands through and in vivo. EP 2 260 858 A2 Printed by Jouve, 75001 PARIS (FR) EP 2 260 858 A2 Description [0001] This application claims the benefit of U.S. Provisional Patent Application No. 60/518,534, filed November 6, 2003; U.S. Provisional Patent Application No. 601557,116, filed March 26, 2004; U.S. Provisional Patent Application 5 No. 60/598,899, filed August 4, 2004; and U.S. Provisional Patent Application No. 60/622,455, filed October 27, 2004; the disclosures of which are incorporated by reference herein. 1. FIELD OF THE INVENTION 10 [0002] The present invention is directed to a Drug Compound and more particularly to Drug-Linker-Ligand Conjugates, Drug-Linker Compounds, and Drug-Ligand Conjugates, to compositions including the same, and to methods for using the same to treat cancer, an autoimmune disease or an infectious disease. The present invention is also directed to antibody-drug conjugates, to compositions including the same, and to methods for using the same to treat cancer, an autoimmune disease or an infectious. disease. The invention also relates to methods of using antibody-drug conjugate 15 compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological con- ditions. 2. BACKGROUND OF THE INVENTION 20 [0003] Improving the delivery of drugs and other agents to target cells, tissues and tumors to achieve maximal efficacy and minimal toxicity has been the focus. of considerable research for many years. Though many attempts have been made to develop effective methods for importing biologically active molecules into cells, both in vivo and in vitro, none has proved to be entirely satisfactory. Optimizing the association of the drug with its intracellular target, while minimizing intercellular redistribution of the drug, e.g., to neighboring cells, is often difficult or inefficient. 25 [0004] Most agents currently administered to a patient parenterally are not targeted, resulting in systemic delivery of the agent to cells and tissues of the body where it is unnecessary, and often undesirable. This may result in adverse drug side effects, and often limits the dose of a drug (e.g., chemotherapeutic (anti-cancer), cytotoxic, enzyme inhibitor agents and antiviral or antimicrobial drugs) that can be administered. By comparison, although oral administration of drugs is considered to be a convenient and economical mode of administration, it shares the same concerns of non- 30 specific toxicity to unaffected cells once the drug has been absorbed into the systemic circulation. Further complications involve problems with oral bioavailability and residence of drug in the gut leading to additional exposure of gut to the drug and hence risk of gut toxicities. Accordingly, a major goal has been to develop methods for specifically targeting agents to cells and tissues. The benefits of such treatment include avoiding the general physiological effects of inap- propriate delivery of such agents to other cells and tissues, such as uninfected cells. Intracellular targeting may be 35 achieved by methods, compounds and formulations which allow accumulation or retention of biologically active agents, i.e. active metabolites, inside cells. [0005] Monoclonal antibody therapy has been established for the targeted treatment of patients with cancer, immu- nological and angiogenic disorders. [0006] The use of antibody-drug conjugates for the local delivery of cytotoxic or cytostatic agents, e.g., drugs to kill 40 or inhibit tumor cells in the treatment of cancer (Syrigos and Epenetos (1999) Anticancer Research 19:605-614; Niculescu- Duvaz and Springer (1997) Adv. Drg. Del. Rev. 26:151-172; U.S. Patent No. 4975278) theoretically allows targeted delivery of the drug moiety to tumors, and intracellular accumulation therein, while systemic administration of these unconjugated drug agents may result in unacceptable levels of toxicity to normal cells as well as the tumor cells sought to be eliminated (Baldwin et al., 1986, Lancet pp. (Mar. 15, 1986):603-05; Thorpe, 1985, "Antibody Carriers Of Cytotoxic 45 Agents In Cancer Therapy: A Review," in Monoclonal Antibodies ’84: Biological And Clinical Applications, A. Pinchera et al. (ed.s), pp. 475-506). Maximal efficacy with minimal toxicity is sought thereby. Both polyclonal antibodies and monoclonal antibodies have been reported as useful in these strategies (Rowland et al., 1986, Cancer Immunol. Immu- nother. 21:183-87). Drugs used in these methods include daunomycin, doxorubicin, methotrexate, and vindesine (Row- land et al., 1986, supra). Toxins used in antibody-toxin conjugates include bacterial toxins such as diphtheria toxin, plant 50 toxins such as ricin, small molecule toxins such as geldanamycin (Kerr et al., 1997, Bioconjugate Chem. 8(6):781-784; Mandler et al. (2000) Jour. of the Nat. Cancer Inst. 92(19):1573-1581; Mandler et al. (2000) Bioorganic & Med. Chem. Letters 10:1025-1028; Mandler et al. (2002) Bioconjugate Chem. 13:786-791), maytansinoids (EP 1391213; Liu et al., (1996) Proc. Natl. Acad. Sci. USA 93:8618-8623), and calicheamicin (Lode et al. (1998) Cancer Res. 58:2928; Hinman et al. (1993) Cancer Res. 53:3336-3342). The toxins may affect their cytotoxic and cytostatic effects by mechanisms 55 including tubulin binding, DNA binding, or topoisomerase inhibition (Meyer, D.L. and Senter, P.D. "Recent Advances in Antibody Drug Conjugates for Cancer Therapy" in Annual Reports in Medicinal Chemistry, Vol 38 (2003) Chapter 23, 229-237). Some cytotoxic drugs tend to be inactive or less active when conjugated to large antibodies or protein receptor ligands. 2 EP 2 260 858 A2 [0007] ZEVALIN® (ibritumomab tiuxetan, Biogen/Idec) is an antibody-radioisotope conjugate composed of a murine IgG1 kappa monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes and 111In or 90Y radioisotope bound by a thiourea linker-chelator (Wiseman et al. (2000) Eur. Jour. Nucl. Med. 27(7):766-77; Wiseman et al. (2002) Blood 99(12):4336-42; Witzig et al. (2002) J. Clin. Oncol. 20(10):2453-63; 5 Witzig et al. (2002) J. Clin. Oncol. 20(15):3262-69). Although ZEVALIN has activity against B-cell non-Hodgkin’s Lym- phoma (NHL), administration results in severe and prolonged cytopenias in most patients. MYLOTARG™ (gemtuzumab ozogamicin, Wyeth Pharmaceuticals), an antibody drug conjugate composed of a hu CD33 antibody linked to calicheam- icin, was approved in 2000 for the treatment of acute myeloid leukemia by injection (Drugs of the Future (2000) 25(7): 686; U.S. Patent Nos. 4970198; 5079233; 5585089; 5606040; 5693762; 5739116; 5767285; 5773001). Cantuzumab 10 mertansine (Immunogen, Inc.), an antibody drug conjugate composed of the huC242 antibody linked via the disulfide linker SPP to the maytansinoid drug moiety, DM1, is advancing into Phase II trials for the treatment of cancers that express CanAg, such as colon, pancreatic, gastric, and others. MLN-2704 (Millennium Pharm., BZL Biologics, Immu- nogen Inc.), ah antibody drug conjugate composed of the anti-prostate specific membrane antigen (PSMA) monoclonal antibody linked to the maytansinoid drug moiety, DM1, is under development for the potential treatment of prostate 15 tumors. The same maytansinoid drug moiety, DM1, was linked through a non-disulfide linker, SMCC, to a mouse murine monoclonal antibody, TA.1 (Chari et al. (1992) Cancer Research 52:127-131). This conjugate was reported to be 200- fold less potent than the corresponding disulfide linker conjugate. The SMCC linker was considered therein to be "non- cleavable." [0008] Several short peptidic compounds have been isolated from the marine mollusc Dolabella auricularia and found 20 to have biological activity (Pettit et al. (1993) Tetrahedron 49:9151; Nakamura et al. (1995) Tetrahedron Letters 36: 5059-5062; Sone et al. (1995) Jour. Org Chem. 60:4474). Analogs of these compounds have also been prepared, and some were found to have biological activity (for a review, see Pettit et al. (1998) Anti-Cancer Drug Design 13:243-277). For example, auristatin E (U.S. Patent No. 5635483) is a synthetic analogue of the marine natural product Dolastatin 10, an agent that inhibits tubulin polymerization by binding to the same domain on tubulin as the anticancer drug vincristine 25 (G.