(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2014/093640 Al 19 June 2014 (19.06.2014) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 47/48 (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, IR, IS, JP, KE, KG, KN, KP, KR, PCT/US20 13/074703 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, 12 December 2013 (12. 12.2013) OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (25) Filing Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (26) Publication Language: English ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/736,483 12 December 2012 (12. 12.2012) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (71) Applicant: MERSANA THERAPEUTICS,INC. UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, [US/US]; 840 Memorial Drive, Cambridge, MA 021 39 TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (US). EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (72) Inventor: YURKOVETSKIY, Aleksander, V.; 2 Old TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Farm Road, Litteton, MA 01460 (US). KM, ML, MR, NE, SN, TD, TG). (74) Agents: ELREIFI, Ivor, R. et al; Mintz Levin Cohn Fer Published: ris Glovsky And Popeo, P , One Financial Center, Boston, MA 021 11 (US). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (54) Title: HYDROXY-POLMER-DRUG-PROTEIN CONJUGATES © (57) Abstract: A drug conjugate is provided herein. The conjugate comprises a protein based recognition-molecule (PBRM) and a polymeric scaffold having one or more -L -D, the PBRM being connected to the polymeric scaffold by Lp, wherein the polymeric o scaffold comprises a linear, branched or cyclic polymer having four or more -OH groups. Each occurrence of D is independently a therapeutic agent having a molecular weight < 5 kDa. L and Lp are linkers connecting the therapeutic agent and PBRM to the poly meric scaffold respectively. Also disclosed are polymeric scaffolds useful for conjugating with a PBRM to form a poly- o mer-drug-PBRM conjugate described herein, compositions comprising the conjugates, methods of their preparation, and methods of treating various disorders with the conjugates or their compositions. HYDROXYL-POLYMER-DRUG-PROTEIN CONJUGATES RELATED APPLICATIONS [0001] This application claims the benefit of and priority to U.S. Provisional Application No. 61/736,483, filed December 12, 2012, the content of which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION [0002] Traditionally, pharmaceuticals have primarily consisted of small molecules that are dispensed orally (as solid pills and liquids) or as injectables. Over the past three decades, formulations (i.e., compositions that control the route and/or rate of drag delivery and allow delivery of the therapeutic agent at the site where it is needed) have become increasingly common and complex. Nevertheless, many questions and challenges regarding the development of new treatments as well as the mechanisms with which to administer them remain to be addressed. For example, many drugs exhibit limited or otherwise reduced potencies and therapeutic effects because they are either generally subject to partial degradation before they reach a desired target in the body, or accumulate in tissues other than the target, or both. [0003] One objective in the field of drug delivery systems, therefore, is to deliver medications intact to specifically targeted areas of the body through a system that can stabilize the drug and control the in vivo transfer of the therapeutic agent utilizing either physiological or chemical mechanisms, or both. [0004] Antibody-drug conjugates have been developed as target-specific therapeutic agents. Antibodies against various cancer cell-surface antigens have been conjugated with different cytotoxic agents that inhibit various essential cellular targets such as microtubules (maytansinoids, auristatins, taxanes: U.S. Patent Nos. 5,208,020; 5,416,064; 6,333,410; 6,441,163; 6,340,701; 6,372,738; 6,436,931; 6,596,757; and 7,276,497); DNA (calicheamicin, doxorubicin, CC-1065 analogs; U.S. Patent Nos. 5,475,092; 5,585,499; 5,846,545; 6,534,660; 6,756,397; and 6,630,579). Antibody conjugates with some of these cytotoxic drugs are actively being investigated in the clinic for cancer therapy (Ricart, A. D., and Tolcher, A. W., 2007, Nature Clinical Practice, 4, 245-255; Krop et al., 2010, J. Clin. Oncol, 28, 2698-2704). However, existing antibody-drag conjugates have exhibited a few limitations. A major limitation is their inability to deliver a sufficient concentration of drug to the target site because of the limited number of targeted antigens and the relatively moderate cytotoxicity of cancer drugs like methotrexate, daunorubicin, maytansinoids, taxanes, and vincristine. One approach to achieving significant cytotoxicity is by linkage of a large number of drug molecules either directly or indirectly to the antibody. However such heavily modified antibodies often display impaired binding to the target antigen and fast in vivo clearance from the blood stream. Therefore, there is a need to improve the ability to deliver a sufficient concentration of a drug to the target such that maximum cytotoxicity for the drug is achieved. SUMMARY OF THE INVENTION [0005] The present invention relates to a protein-hydroxyl polymer-drug conjugate that is biodegradable, biocompatible and exhibits high drug load as well as strong binding to target antigen. The present invention also relates to a polymeric scaffold useful to conjugate with a protein based recognition-molecule (PBRM) so as to obtain the protein-hydroxyl polymer-drug conjugate. [0006] In one aspect, the invention features a polymeric scaffold useful to conjugate with a PBRM. The scaffold includes a linear, branched or cyclic polymer having one or more -OH (0) -C(=0)-L Di- - groups connected to the polymer, one or more u D connected to the P2 — (0) u-C(=0)-L^-L polymer, and one or more connected to the polymer, wherein: the polymer is a hydroxyl polymer, each occurrence of D is independently a therapeutic agent having a molecular weight < 5 kDa; LD is a carbonyl-containing moiety; D D (0) u-C(=0)-L i- _ (0) -C(=0)-L ^-D each occurrence of in independently is a first linker that contains a biodegradable bond so that when the bond is broken, D is released in an active form for its intended therapeutic effect; in which each u D - - (0) u-C(=0)-L i - - D D independently is an integer 0 or 1, and the in between L and D denotes direct or indirect attachment of D to LD 1; and each occurrence of is independently a second linker not yet connected to PBRM in which L is a moiety containing a functional group that is capable of forming a covalent bond with a functional roup of a PBRM, each u independently is an integer 0 or 1, and the in denotes direct or indirect attachment of L 2 to LD , and each occurrence of the second linker is distinct from each occurrence of the first linker. [0007] The polymeric scaffold can include one or more of the following features: [0008] The hydroxyl polymer has a molecular weight ranging from 2 kDa to 300 kDa. [0009] The polymeric carrier (e.g., hydroxyl polymer), is not a polyacetal or a polyketal. The polymeric carrier is not poly(l-hydroxymethylethylene hydroxymethyl-formal, PHF). [0010] The polymeric carrier is not a polysaccharide, carbohydrate, or oligosaccharide. [001 1] The polymeric carrier is not a naturally-occurring polymer selected from polysaccharide, carbohydrate, and oligosaccharide. [0012] The polymeric carrier is selected from hydroxyalkyl starches, polyglycerols, PEG polymers, HPMA polymers, carboxymethyl dextrans (CM dextrans), polyvinyl alcohols, poly(acrylic acid), and dendrimers, copolymers and mixtures thereof. [0013] The polymeric carrier has at least four -OH groups before modification. [0014] When the one or more -OH groups are the hydroxyl groups of one or more -COOH connected to the polymeric carrier, u is 0. [0015] When the one or more -OH groups are not the hydroxyl groups of one or more -COOH, u is 1. [0016] LD is a carbonyl-containing moiety. D 1 [0017] L comprises —X-(CH )v-C(=0) — with X directly connected to the carbonyl group of -(0)u-C(=0), in which X is CH2, O, or NH, and v is an integer from 1 to 6. [0018] L 2 contains a biodegradable bond. [0019] The functional group of L 2 is selected from -SR , -S-S-LG, maleimido, and halo, in which LG is a leaving group and Rp is H or a sulfur protecting group. [0020] The polymer of the scaffold of the invention is a linear, branched or cyclic hydroxyl polymeric carrier having a molecular weight ranging from 2 kDa to 300 kDa. (i.e., MW of the unmodified hydroxyl polymer) and the hydroxyl polymer is not a polyacetal or polyketal.