(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property WO 2014/189973 A2 Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/189973 A2 27 November 2014 (27.11.2014) WIPO I PCT (51) International Patent Classification: (71) Applicant (for AL, AT, BE, BG, CH, CN, CY, CZ, DE, DK, C07K16/28 (2006.01) EE, ES, FI, FR, GB, CR, HR, HU, IE, IN, IS, IT, LT, LU, LV, MC, M K MT.I NL, NO, PL, PT, RO, RS, SE, SI, SK (21) International Application Number: SM, TR only)·. F. HOFFMANN-LA ROCHE AG PCT/US2014/038847 [CH/CH]; Grenzacherstrasse 124, CH-4070 Basel (CH). (22) International Filing Date: (72) Inventors: ZHANG, Yin; c/o Genentech, Inc., I DNA 20 May 2014 (20.05.2014) Way, South San Francisco, California 94080 (US). (25) Filing Language: English ZUCHERO, Joy Yu; c/o Genentech, Inc., I DNA Way, South San Francisco, California 94080 (US). ATWAL, (26) Publication Language: English Jasvinder; c/o Genentech, Inc., I DNA Way, South San (30) Priority Data: Francisco, California 94080 (US). COUCH, Jessica; c/o 61/825,477 20 May 2013 (20.05.2013) US Genentech, Inc., I DNA Way, South San Francisco, Cali­ fornia 94080 (US). DENNIS, Mark; c/o Genentech, Inc., I (71) Applicant (for all designated States except AL, AT, BE, DNA Way, South San Francisco, California 94080 (US). BG, CH, CN, CY, CZ, DE, DK, EE, ES, FI, FR, GB, CR, ERNST, James; c/o Genentech, Inc., I DNA Way, South HR, HU, IE, IN, IS, IT, LT, LU, LV, MC, MK, MT, NL, San Francisco, California 94080 (US). WATTS, Ryan; c/o NO, PL, PT.: RO, RS, SE, SI, SK SM, TR): GENENTECH, Genentech, Inc., I DNA Way, South San Francisco, Cali­ INC. [US/US]; I Dna Way, South San Francisco, Califor­ fornia 94080 (US). LAZAR, Gregory A.; c/o Genentech, nia 94080 (US). Inc., I DNA Way, South San Francisco, California 94080 (US). [Continued on next page] (54) Title: ANTI-TRANSFERRIN RECEPTOR ANTIBODIES AND METHODS OF USE (57) Abstract: The present invention relates to anti-transfer - rin receptor antibodies and methods of their use. WO 2014/189973 A l WO 2014/189973 A2 (74) Agents: HEEDER, Julie A. et al.; Genentech, Inc., Mail (84) Designated States (unless otherwise indicated, for every Stop 49, South San Francisco, California 94080 (US). kind o f regional protection available)·. ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (81) Designated States (unless otherwise indicated, for every UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, kind o f national protection available)·. AE, AG, AL, AM, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, SM, TR), OAPI (BF, BJ, CF, CO, Cl, CM, GA, GN, GQ, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, GW, KM, ML, MR, NE, SN, TD, TG). KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NO, Published: NI, NO, NZ, OM, PA, PE, PO, PH, PL, PT, QA, RO, RS, — without international search report and to be republished RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, upon receipt o f that report (Rule 48.2(g)) TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. — with sequence listing part o f description (Rule 5.2(a)) WO 2014/189973 PCT/US2014/038847 ANTI-TRANSFERRIN RECEPTOR ANTIBODIES AND METHODS OF USE 5 FIELD OF THE INVENTION The present invention relates to anti-transferrin receptor antibodies and methods of using the same. RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 61/825,477 10 filed on May 20, 2013, of which is incorporated by reference herein in its entirety. SEQUENCE LISTING A sequence listing is submitted concurrently with the specification as an ASCII formatted text file via EFS-Web, with a file name of “P5641Rl-WO_SL.txt”, a creation date of May 16, 2014, and a size of 154,599 bytes. The sequence listing filed via EFS-Web is part of 15 the specification and is hereby incorporated by reference in its entirety herein. BACKGROUND Brain penetration of large molecule drugs is severely limited by the largely impermeable blood-brain barrier (BBB). Among the many strategies to overcome this obstacle is to utilize transcytosis trafficking pathways of endogenous receptors expressed at the brain 20 capillary endothelium. Recombinant proteins such as monoclonal antibodies have been designed against these receptors to enable receptor-mediated delivery of large molecules to the brain. Strategies to maximize brain uptake while minimizing reverse transcytosis back to the blood, and to also maximize the extent of accumulation after therapeutic dosing have been addressed with the finding that antibodies with low affinity to BBB receptors offer the potential 25 to substantially increase BBB transport and CNS retention of associated therapeutic moieties/molecules relative to typical high-affmity antibodies to such receptors (Atwal et al., Sci. Transl. Med. 3, 84ra43 (2011); Yu et al., Sci. Transl. Med. 25 May 2011: Vol. 3, Issue 84, p. 84ra44). However, those antibodies did not specifically bind to human and primate TfR. SUMMARY 30 Monoclonal antibodies have vast therapeutic potential for treatment of neurological or central nervous system (CNS) diseases, but their passage into the brain is restricted by the I WO 2014/189973 PCT/US2014/038847 blood-brain barrier (BBB). Past studies have shown that a very small percentage (approximately 0.1%) of an IgG circulating in the bloodstream crosses through the BBB into the CNS (Felgenhauer, Klin. Wschr. 52: 1158-1164 (1974)), where the CNS concentration of the antibody may be insufficient to permit a robust effect. It was previously found that the 5 percentage of the antibody that distributes into the CNS could be improved by exploiting BBB receptors (ie, transferrin receptor, insulin receptorand the like) (see, e.g., WO9502421). For example, the anti-BBB receptor antibody can be made multispecific to target one or more desired antigens in the CNS, or one or more heterologous molecules can be coupled to the anti- BBB receptor antibody; in either case, the anti-BBB receptor antibody can assist in delivering a 10 therapeutic molecule into the CNS across the BBB. However, targeting a BBB receptor with a traditional specific high-affinity antibody generally resulted in limited increase in BBB transport. It was later found by Applicants that the magnitude of antibody uptake into and distribution in the CNS is inversely related to its binding affinity for the BBB receptor amongst the anti-BBB antibodies studied. For example, a 15 low-affinity antibody to transferrin receptor (TfR) dosed at therapeutic dose levels greatly improves BBB transport and CNS retention of the anti-TfR antibody relative to a higher- affinity anti-TfR antibody, and makes it possible to more readily attain therapeutic concentrations in the CNS (Atwal et al., Sci. Transl. Med. 3, 84ra43 (2011)). Proof of such BBB transport was achieved using a bispecific antibody that binds both TfR and the amyloid 20 precursor protein (APP) cleavage enzyme, β-secretase (BACE1). A single systemic dose of the bispecific anti-TfR/BACEl antibody engineered using the methodology of the invention not only resulted in significant antibody uptake in brain, but also dramatically reduced levels of brain Αβι_ 4ο compared to monospecific anti-BACEl alone, suggesting that BBB penetrance affects the potency of anti-BACEl. (Atwal et al., Sci. Transl. Med. 3, 84ra43 (2011); Yu et al., 25 Sci. Transl. Med. 3, 84ra44 (2011)). Those data and experiments highlighted several causative mechanisms behind increasing uptake of an antibody into the CNS using a lower-affinity antibody approach. First, high affinity anti-BBB receptor (BBB-R) antibodies (e.g., anti-TfRA from Atwal et al. and Yu et al., supra ) limit brain uptake by quickly saturating the BBB-R in the brain vasculature, thus 30 reducing the total amount of antibody taken up into the brain and also restricting its distribution to the vasculature. Strikingly, lowering affinity for the BBB-R improves brain uptake and distribution, with a robust shift observed in localization from the vasculature to neurons and associated neuropil distributed within the CNS. Second, the lower affinity of the antibody for the BBB-R is proposed to impair the ability of the antibody to return to the vascular side of the 2 WO 2014/189973 PCT/US2014/038847 BBB via the BBB-R from the CNS side of the membrane because the overall affinity of the antibody for the BBB-R is low and the local concentration of the antibody on the CNS side of the BBB is non-saturating due to the rapid dispersal of the antibody into the CNS compartment. Third, in vivo, and as observed for the TfR system, antibodies with less affinity for the BBB-R 5 are not cleared from the system as efficiently as those with greater affinity for the BBB-R, and thus remain at higher circulating concentrations than their higher-affinity counterparts. This is advantageous because the circulating antibody levels of the lower-affinity antibody are sustained at therapeutic levels for a longer period of time than the higher-affinity antibody, which consequently improves uptake of antibody in brain for a longer period of time.