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WO 2018/027204 Al 08 February 2018 (08.02.2018) W !P O PCT

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WO 2018/027204 Al 08 February 2018 (08.02.2018) W !P O PCT (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 2018/027204 Al 08 February 2018 (08.02.2018) W !P O PCT (51) International Patent Classification: only): F. HOFFMANN-LA ROCHE AG [CH/CH]; Gren- C07K 16/28 (2006.01) A61K 39/00 (2006.01) zacherstrasse 124, 4070 Basel (CH). (21) International Application Number: (72) Inventor; and PCT/US20 17/045642 (71) Applicant: HARRIS, Seth [US/US]; c/o Genentech, Inc., 1 DNA Way, South San Francisco, California 94080 (US). (22) International Filing Date: 04 August 2017 (04.08.2017) (72) Inventors: LAZAR, Greg; c/o Genentech, Inc., 1 DNA Way, South San Francisco, California 94080 (US). YANG, (25) Filing Language: English Yanli; c/o Genentech, Inc., 1 DNA Way, South San Fran (26) Publication Language: English cisco, California 94080 (US). CHRISTENSEN, Erin H.; c/ o Genentech, Inc., 1 DNA Way, South San Francisco, Cali (30) Priority Data: fornia 94080 (US). HANG, Julie; 6606 Wisteria Way, San 62/371,671 05 August 2016 (05.08.2016) US Jose, California 95 129 (US). KIM, Jeong; c/o Genentech, (71) Applicant (for all designated States except AL, AT, BA, BE, Inc., 1 DNA Way, South San Francisco, California 94080 BG, CH, CN, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, (US). HR, HU, IE, IN, IS, IT, LT, LU, LV, MC, MK, MT, NL, (74) Agent: JONES, Kevin et al; Morrison & Foerster LLP, NO, PL, PT RO, RS, SE, SI, SK, SM, TR): GENENTECH, 425 Market Street, San Francisco, California 94105-2482 INC. [US/US]; 1 DNA Way, South San Francisco, Califor (US). nia 94080-4990 (US). (81) Designated States (unless otherwise indicated, for every (71) Applicant (for AL, AT, BE, BG, CH, CN, CY, CZ, DE, DK, kind of national protection available): AE, AG, AL, AM, EE, ES, FI, FR, GB, GR, HR, HU, IE, IN, IS, IT, LT, LU, LV, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (54) Title: MULTIVALENT AND MULTIEPITOPIC ANITIBODIES HAVING AGONISTIC ACTIVITY AND METHODS OF USE IgG c:lgG-lgG c:Fab-!gG r:Fab-igG r:Fv-lgG Biepitopic FIG. l o (57) Abstract: Provided herein are tetravalent antigen binding complexes having agonist activity for a cell surface receptor. In some 00 embodiments, the complexes comprise binding specificities for multiple epitopes of the same cell surface receptor. Further provided © herein are nucleic acids, vectors, host cells, pharmaceutical compositions, and methods of production related thereto. O [Continued on nextpage] WO 2018/027204 Al llll II II 11III II I II 11III I II II III II I II DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 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, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 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, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3)) — with sequence listing part of description (Rule 5.2(a)) MULTIVALENT AND MULTIEPITOPIC ANTIBODIES HAVING AGONISTIC ACTIVITY AND METHODS OF USE CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the priority benefit of U.S. Provisional Application Serial No. 62/371,671, filed August 5, 2016, which is hereby incorporated by reference in its entirety. SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE [0002] The content of the following submission on ASCII text file is incorporated herein by reference in its entirety: a computer readable form (CRF) of the Sequence Listing (file name: 146392037740SEQLIST.txt, date recorded: August 4, 2017, size: 353 KB). FIELD OF THE INVENTION [0003] The present invention relates to multivalent and multiepitopic antigen binding complexes having agonistic activity and methods of using the same. BACKGROUND [0004] Functional antibodies and antigen binding complexes are an important therapeutic option for treatment of a wide variety of diseases. There is a need in the art for better means for identifying functional antibodies and antigen binding complexes, particularly those having agonistic activity, from pools of candidate molecules. There is a further need in the art for antibodies and antigen binding complexes with more potent agonistic activity. The present invention is directed to these and other needs. [0005] The disclosures of all patent and scientific literature cited herein are expressly incorporated in their entirety by reference. SUMMARY [0006] The invention provides antigen binding complexes (e.g., multivalent and multiepitopic antibodies/antigen binding complexes) having agonistic activity and methods of using the same. [0007] In one aspect, provided herein is a tetravalent antigen binding complex having agonist activity, the complex comprising: a first and a second subunit, wherein each of the first and the second subunits comprises: (i) a first half-antibody comprising a first antibody heavy chain variable domain (VHi) and a first antibody light chain variable domain (VLi), wherein the first half-antibody specifically binds to a first epitope of a cell surface receptor, and (ii) a second half-antibody comprising a second antibody heavy chain variable domain (VH2) and a second antibody light chain variable domain (VL2), wherein the second half- antibody specifically binds to a second epitope of the cell surface receptor; wherein the first and the second subunits are coupled, and wherein the complex has agonist activity for the cell surface receptor bound by the complex. In some embodiments, an antigen binding complex of the present disclosure shows agonist activity in vitro. In some embodiments, each of the first and the second subunits comprises: (i) the first half-antibody, wherein the first half- antibody comprises: (a) a first antibody heavy chain comprising, from N-terminus to C- terminus, the first antibody heavy chain variable domain (VHi), a first antibody heavy chain CHI domain, a first antibody heavy chain CH2 domain, and a first antibody heavy chain CH3 domain; and (b) a first antibody light chain comprising, from N-terminus to C-terminus, the first antibody light chain variable domain (VLi) and a first antibody light chain constant domain (CL); and (i) the second half-antibody, wherein the second half- antibody comprises: (a) a second antibody heavy chain comprising, from N-terminus to C-terminus, the second antibody heavy chain variable domain (VH2), a second antibody heavy chain CHI domain, a second antibody heavy chain CH2 domain, and a second antibody heavy chain CH3 domain; and (b) a second antibody light chain comprising, from N-terminus to C-terminus, the second antibody light chain variable domain (VL2) and a second antibody light chain constant domain (CL). In some embodiments, the first and the second subunits are chemically coupled. In some embodiments, the first and the second epitopes of the cell surface receptor are the same. In some embodiments, the first and the second epitopes of the cell surface receptor are different. In some embodiments, each of the first and the second subunits comprises a bispecific antibody, the bispecific antibody comprises two antibody Fc regions with two CH3 domains, each of the two CH3 domains comprises either a protuberance or a cavity, and the protuberance or cavity in the first of the two CH3 domains is positionable in the cavity or protuberance, respectively, in the second of the two CH3 domains. In some embodiments, the two subunits are chemically coupled via a linker. In some embodiments, each of the two subunits comprises two heavy chains and two light chains, and one of the heavy chains of each subunit comprises a cysteine amino acid in the heavy chain selected from T114C, A118C, A140C, L174C, L179C, T187C, T209C, V262C, G371C, Y373C, E382C, S400C, S424C, N434C and Q438C, according to EU numbering. In some embodiments, each of the two subunits comprises two heavy chains and two light chains, and one of the light chains of each subunit comprises a cysteine amino acid in the light chain selected from I106C, R108C, R142C, K149C, and V205C, according to Kabat numbering. In some embodiments, the two subunits are chemically coupled via click chemistry. In some embodiments, the two subunits are coupled via a tetrazine-transcyclooctene (TCO) click reaction. In some embodiments, the linker is between about 10A and about 100A in length. In some embodiments, the linker is a bis-maleimido polyethylene glycol (PEG) linker. In some embodiments, the PEG linker comprises between one and eleven PEG subunits. In some embodiments, the PEG linker comprises one, two, or three PEG subunits. In some embodiments, each of the subunits comprises an Fc region comprising a modification for attenuating effector function. In some embodiments, each of the subunits comprises an Fc region comprising an amino acid substitution at one or more amino acid residues (EU numbering) selected from (a) 297 in the Fc region of human IgGl, (b) 234 and 235 in the Fc region of human IgGl, (c) 234, 235 and 329 in the Fc region of human IgGl, (d) 234 and 237 in the Fc region of human IgG2, (e) 235, 237 and 318 in the Fc region of human IgG4, (f) 228 and 236 in the Fc region of human IgG4, (g) 268, 309, 330 and 331 in the Fc region of human IgG2, (h) 220, 226, 229 and 238 in the Fc region of human IgGl, (i) 226, 229, 233, 234 and 235 in the Fc region of human IgGl, (j) 234, 235 and 331 in the Fc region of human IgGl, (k) 226 and 230 in the Fc region of human IgGl, and (1) 267 and 328 in the Fc region of human IgGl.
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