(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 2016/071856 Al 12 May 2016 (12.05.2016) P O P C T (51) International Patent Classification: (74) Agent: RAYMOND, Daniel E ; c/o Novartis Pharmaceut C07K 7/64 (2006.01) A61P 35/00 (2006.01) icals Corporation, IP Services Mail Data, One Health Plaza A61K 38/12 (2006.01) 101/2, East Hanover, New Jersey 07936 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/IB2015/058537 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) Date: International Filing BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 5 November 20 15 (05 .11.20 15) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (26) Publication Language: English MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (30) Priority Data: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 62/076,023 6 November 2014 (06. 11.2014) US 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. (71) Applicant (for all designated States except US) : NO- VARTIS AG [CH/CH]; Lichtstrasse 35, CH-4056 Basel (84) Designated States (unless otherwise indicated, for every (CH). kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (72) Inventors; and TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (71) Applicants (for US only): GRUNEWALD, Jan [DE/US]; TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Novartis Institute for Functional Genomics, Inc., Genomics DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Institute of the Novartis Research Foundation (GNF), LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 10675 John Jay Hopkins Drive, San Diego, California SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, 9212 1 (US). JIN, Yunho [KR/US]; Novartis Institute for GW, KM, ML, MR, NE, SN, TD, TG). Functional Genomics, Inc., Genomics Institute of the No vartis Research (GNF), 10675 John Jay Hopkins Drive, Declarations under Rule 4.17 : San Diego, California 92 121 (US). OU, Weijia [US/US]; — as to applicant's entitlement to apply for and be granted a Novartis Institute for Functional Genomics, Inc., Genomics patent (Rule 4.1 7(H)) Institute of the Novartis Research (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121 (US). UNO, Published: Tetsuo [JP/US]; Novartis Institute for Functional Genom — with international search report (Art. 21(3)) ics, Inc., Genomics Institute of the Novartis Research — with sequence listing part of description (Rule 5.2(a)) (GNF), 10675 John Jay Hopkins Drive, San Diego, Cali fornia 92121 (US). (54) Title: AMATOXIN DERIVATIVES AND CONJUGATES THEREOF AS INHIBITORS OF RNA POLYMERASE FIG. 4 00 © † Days Post Implantation (57) Abstract: The invention disclosed herein relates to cytotoxic cyclic peptides of Formula (I), methods of inhibiting RNA poly o merase with such cyclic peptides, immunoconjugates comprising such cyclic peptides (i.e Antibody Drug Conjugates), pharmaceut ical compositions comprising such cyclic peptides immunoconjugates, compositions comprising such cyclic peptides immunocon - jugates with a therapeutic co-agent and methods of treatment using such cyclic peptides immunoconjugates: Formula (I). AMATOXIN DERIVATIVES AND CONJUGATES THEREOF AS INHIBITORS OF RNA POLYMERASE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62/076023, filed 06 November 201 4 , which is incorporated by reference herein in its entirety. F IELD OF THE INVENTION The invention relates to amatoxins and conjugates of amatoxins to a target-binding moiety, e.g. an antibody, and the use of such conjugates to treat cancer. BACKGROUND Amatoxins are cyclic peptides comprised of eight amino acid units which can be prepared synthetically, or can be isolated from a variety of mushroom species, such as Amanita phalloides (green death cap mushroom), Amanita bisporigera (destroying angel) , Amanita ocreata (destroying angel) , Amanita virosa (destroying angel) , Amanita bisporigera (fool's mushroom), Lepiota brunneo-incamata (deadly dapperling), Conocybe tiiaris and Galerina marginata. There are currently ten known members of the Amatoxin Family: alpha-Amanitin , beta-Amanitin , gamma-Amanitin, epsilon-Amanitin , Amanullin , Amanullinic acid, Amaninamide, Amanin and Proamanullin. Different mushroom species contain varying amounts of different Amatoxin family members. Amatoxins are potent and selective inhibitors of RNA polymerase II, a vital enzyme in the synthesis of messenger RNA (mRNA), microRNA, and small nuclear RNA (sn RNA). By inhibiting the synthesis of mRNA, Amatoxins thereby stop cell metabolism by inhibiting transcription and protein biosynthesis, which results in cellular apoptosis. Consequently Amatoxins stop cell growth and proliferation. Alpha-amanitin, is known to be an extremely potent inhibitor of eukaryotic RNA polymerase II (EC2.7.7.6) and to a lesser degree, RNA polymerase II I, thereby inhibiting transcription and protein biosynthesis. Wieland ( 1983) Int. J. Pept. Protein Res. 22(3) :257-276. Alpha-amanitin binds non-covalently to RNA polymerase II and dissociates slowly, making enzyme recovery unlikely. The use of antibody-drug conjugates (ADCs) for the targeted delivery of cell proliferation inhibitors and/or cytotoxic agents to specific cells has been the focus of significant research. Antibody-Drug Conjugate, Methods in Molecular Biology, Vol. 1045, Editor L . Ducry, Humana Press (201 3). ADCs include an antibody selected for its ability to bind to a cell targeted for therapeutic intervention , linked to a drug selected for its cytostatic or cytotoxic activity. Binding of the antibody to the targeted cell thereby delivers the drug to the site where its therapeutic effect is needed. Many antibodies that recognize and selectively bind to targeted cells, like cancer cells, have been disclosed for use in ADCs, and many methods for attaching payload (drug) compounds such as cytotoxins to antibodies have also been described. In spite of the extensive work on ADCs, though, only a few classes of cell proliferation inhibitors have been used extensively as ADC payloads. Even though the first ADC approved for use in humans in the U.S. was launched in 2000 (and later withdrawn from the market), a decade later only a few chem ical classes of drug compounds (maytansinoids, auristatins, calicheamycins and duocarmycins) had reached clinical trials as payloads for ADCs. Antibody-Drug Conjugates: the Next Generation of Moving Parts, A . Lash, Start-Up , Dec. 201 1, 1-6. The use of amatoxins as cytotoxic moieties in ADC's for tumour therapy was explored in 1981 (Davis & Preston, Science 1981 , 2 13 , 1385-1 388) by coupling an anti-Thy 1.2 antibody to alpha-amanitin using a linker attached to the 7' position of the indole ring via diazotation. Morris & Venton (Morris & Venton, Int. J. Peptide Protein Res. 1983, 2 1 4 19- 430) also demonstrated that substitution at the 7' position resulted in a derivative which maintained cytotoxic activity. Patent application EP 1 859 8 1 1 A 1 (published November 28, 2007) described the direct conjugation (i.e. without a linker structure) of albumin or a monoclonal antibody (HEA1 25, OKT3, or PA-1) to the gamma C-atom of amatoxin amino acid 1 of beta- amanitin . The inhibitory effect of these conjugates on the proliferation of breast cancer cells (MCF-7), Burkitt's lymphoma cells (Raji), and Tlymphoma cells (Jurkat) was shown. The use of linkers was suggested, however no such constructs were exemplified and no details regarding linker attachment sites on Amatoxins were provided. Patent applications WO 201 0/1 15629 and WO 201 0/1 15630 (both published October 14 , 201 0) describe conjugates, where antibodies, such as antiEpCAM antibodies such as humanized antibody huHEA1 25, are coupled to amatoxins via (i) the gamma C-atom of amatoxin amino acid 1, (ii) the 6' C-atom of amatoxin amino acid 4 , or (iii) via the delta C- atom of amatoxin amino acid 3 , in each case either directly or via a linker between the antibody and the amatoxins. The inhibitory effects of these conjugates on the proliferation of breast cancer cells (cell line MCF-7), pancreatic carcinoma (cell line Capan-1 ) , colon cancer (cell line Colo205) and cholangiocarcinoma (cell line OZ) were shown. Patent applications WO 201 2/1 19787 (published September 13 , 201 2) describes conjugating a target-binding moiety via a linker attached to the amatoxin indole nitrogen. The cytotoxic activity of such conjugates on a HER2-positive tumor cell line in vitro was disclosed. Patent applications WO 201 4/043403 (published March 20, 201 4) describes conjugating a target-binding moiety via a linker attached to the T position of the amatoxin indole. The cytotoxic activity of such conjugates on Herceptin and lgG1 in MDA-MB-468 cells was disclosed. Also, the cytotoxic activity of such conjugates on Herceptin in PC3, HCC-1 954 and MDA-MB-46 cells was disclosed. In view of the toxicity of amatoxins, particularly for liver cells, it is important that ADC's comprising a linked amatoxin remain highly stable in plasma prior to the release of the amatoxin after internalization into the target cells. In this regard, improvements of the conjugate stability may have drastic consequences for the therapeutic window and the safety of the amatoxin conjugates for therapeutic approaches.