WO 2012/162561 A2 29 November 2012 (29.11.2012) P O P C T
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(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 2012/162561 A2 29 November 2012 (29.11.2012) P O P C T (51) International Patent Classification: (74) Agents: SHEA, Timothy J., Jr. et al; 1100 New York C07K 16/00 (2006.01) Avenue N.W., Washington, District of Columbia 20005- 3934 (US). (21) International Application Number: PCT/US20 12/039469 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) Date: International Filing AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, 24 May 2012 (24.05.2012) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (25) Filing Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, (26) Publication Language: English KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (30) Priority Data: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 61/489,249 24 May 201 1 (24.05.201 1) OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, 61/597,714 10 February 2012 (10.02.2012) SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, 61/610,83 1 14 March 2012 (14.03.2012) TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant (for all designated States except US): ZYN- (84) Designated States (unless otherwise indicated, for every GENIA, INC. [US/US]; 2 1 First Field Road, Suite 200, kind of regional protection available): ARIPO (BW, GH, Gaithersburg, Maryland 20878 (US). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (72) Inventors; and TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (75) Inventors/Applicants (for US only): ROSCHKE, Viktor EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, [US/US]; 4702 West Virginia Avenue, Bethesda, Maryland MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 20814 (US). LAFLEUR, David [US/US]; 3142 Quesada TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Street, N.W., Washington, District of Columbia 20015 ML, MR, NE, SN, TD, TG). (US). HILBERT, David M. [US/US]; 5801 Meadowlark Lane, Bethesda, Maryland 20817 (US). KIENER, Peter Published: [US/US]; 14017 Gorky Drive, Potomac, Maryland 20854 — without international search report and to be republished (US). upon receipt of that report (Rule 48.2(g)) (54) Title: MULTIVALENT AND MONOVALENT MULTISPECIFIC COMPLEXES AND THEIR USES < FIG. 2 (57) Abstract: Compositions containing multivalent and monovalent multispecific complexes having scaffolds, such as antibodies, o© that support such binding functionalities are described. The use of and methods of compositions containing multivalent and mono - valent multispecific complexes having scaffolds, such as antibodies, that support such binding functionalities are also described. MULTIVALENTAND MONOVALENTMULTISPECIFIC COMPLEXES AND THEIR USES BACKGROUND OF THE INVENTION Field of the Invention [0001] This invention relates generally to compositions containing multivalent multispecific complexes and to compositions containing multivalent and monovalent multispecific complexes having scaffolds, such as antibodies, that support such binding functionalities. The invention also generally relates to methods of making these multispecific compositions and the diagnostic and therapeutic uses of these compositions. Background [0002] n recent years, drug discovery efforts have primarily focused on identifying agents that modulate preselected individual targets. However, agents directed to individual targets frequently show limited efficacies and poor safety and resistance profiles, as a result of the robustness, redundancy, crosstalk, compensatory signaling networks and anti- or counter- signaling network activities associated with the therapeutic target. Consequently, drug discovery efforts have increasingly been directed toward the discovery of new multicomponent based therapies. [0003] The development of bispecific or multi-specific molecules that target two or more targets simultaneously offers a novel and promising solution for discovering new systems- oriented multitargeted agents demonstrating improved efficacy and pharmacological properties over conventional monotherapies. Numerous attempts to develop multispecific molecules have been based on immunoglobulin-like domains or subdomains. For example, traditionally, bispecific antibodies have been prepared by chemically linking two different monoclonal antibodies or by fusing two hybridoma cell lines to produce a hybrid-hybridoma. Other immunoglobulin-like domain-based technologies that have created multispecific, and/or multivalent molecules include dAbs, diabodies, TandAbs, nanobodies, BiTEs, SMIPs, DNLs, Affibodies, Fynomers, Kunitz Domains, Albu-dabs, DARTs, DVD-iG, Covx-bodies, peptibodies, scFv-lgs, SVD-Igs, dAb-Igs, Knobs-in-Holes, DuoBodies™ and triomAbs. Although each of these molecules may bind one or more targets, they each present challenges with respect to retention of typical Ig function (e.g., half-life, effector function), production (e.g., yield, purity), valency, simultaneous target recognition, and bioavailability. [0004] Other attempts to generate multispecific and multivalent molecules have relied on alternative scaffolds, based VASP polypeptides, Avian pancreatic polypeptide (aPP), Tetranectin (based on CTLD3), Affilin (based on γ β -crystallin/ubiquitin), knottins, SH3 domains, PDZ domains, Tendamistat, Transferrin, an ankyrin consensus repeat domain (e.g., DARPins), lipocalin protein folds (e.g., Duocalins), fibronectin (see for example, US Application Publ. Nos. 2003/0170753 and 20090155275 which are herein incorporated by reference), a domain of protein A (e.g., Affibodies), thioredoxin. Other attempts have relied on alternative scaffolds fuse or associate polypeptides of interest with albumin (e.g., ALBUdAb (Domantis/GSK) and ALB-Kunitz (Dyax)), unstructured repeat sequences of 3 or 6 amino acids (e.g., PASylation® technology and XTEN® technology), and sequences containing elastin-like repeat domains (see for example, U.S. Pat. Appl. No. 61/442,106, which is herein incorporated by reference). To date, these technologies have demonstrated limited clinical potential as robust platforms for developing diverse multispecific and multivalent therapeutic compositions. [0005] The genetic complexity of most human malignancies and other disorders strongly suggest that interfering with a single target or pathway associated with these disorders is unlikely to produce optimal or sustained therapeutic benefit. There is, therefore, a great need for developing multispecific and multivalent therapeutics such as multispecific antibodies that are capable of interfering with the activity of multiple targets and/or signaling mechanisms in or to optimize the therapeutic benefits of treatments directed towards these disorders. BRIEF SUMMARY OF THE INVENTION [0006] The invention relates to compositions containing multivalent as well as multivalent and monovalent, multispecific complexes having scaffolds, such as antibodies, that support such binding functionalities. The invention is based in part on the surprising discovery that multispecific and multivalent binding compositions, such as those generated using the ZYBODY™ platform (Zyngenia, Inc.; see, e.g., Intl. Pub. No. W0 2009/088805 which is erein incorporated by reference) demonstrate dramatic synergistic biological activity compared to conventional monotherapy combinations. This synergistic activity is expected to extend to novel therapies, for treating or preventing cancer, diseases or disorders of the immune system (e.g., autoimmune diseases such as, rheumatoid arthritis, and IBD), skeletal system (e.g., osteoporosis), cardiovascular system (e.g., stroke, heart disease), nervous system (e.g., Alzheimer's), infectious disease (e.g., HIV), and other diseases or disorders described herein or otherwise known in the art. [0007] In one embodiment, the invention is directed to treating a disease or disorder by administering a therapeutically effective amount of a multivalent and monovalent multispecific composition to a patient in need thereof. In a further embodiment, the invention is directed to treating a disease or disorder by administering a therapeutically effective amount of a multivalent and multispecific MRD-containing antibody to a patient in need thereof. [0008j In one embodiment, the multivalent and monovalent multispecific composition contains 2 binding sites for three or more targets. In an additional embodiment, the multivalent and monovalent multispecific composition contains 2 binding sites for four or more targets. In another embodiment, the multivalent and monovalent multispecific composition contains 2 binding sites for five or more targets. According to some embodiments, at least 1, 2, 3, 4 or more of the targets are located on a cell surface. According to some embodiments, at least 1, 2, 3, 4 or more of the targets are soluble targets (e.g., chemokines, cytokines, and growth factors). In additional embodiments, the multivalent and monovalent multispecific composition binds 1, 2, 3, 4 or more of the targets described herein. [0009] In additional embodiments, the targets bound by the multivalent and monovalent multispecific composition are associated with cancer. In a further embodiment the targets bound by the multivalent and monovalent multispecific composition are associated with 1, 2, 3, 4 or more different