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C07K 16/28 (2006.01) (21) International Application Number

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C07K 16/28 (2006.01) (21) International Application Number ( 2 (51) International Patent Classification: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, A61K 39/00 (2006.01) C07K 16/28 (2006.01) SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW. (21) International Application Number: PCT/US2020/033563 (84) Designated States (unless otherwise indicated, for every kind of regional protection available) . ARIPO (BW, GH, (22) International Filing Date: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, 19 May 2020 (19.05.2020) UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (25) Filing Language: English 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, (26) Publication Language: English MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (30) Priority Data: TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, 62/850,889 2 1 May 2019 (21.05.2019) US KM, ML, MR, NE, SN, TD, TG). 62/854,667 30 May 2019 (30.05.2019) US Declarations under Rule 4.17: (71) Applicant: NOVARTIS AG [CH/CH]; Lichtstrassc 35, — as to applicant's entitlement to apply for and be granted a 4056 Basel (CH). patent (Rule 4.17(H)) (71) Applicant (for US only): HUANG, Lu [US/US]; Novartis — as to the applicant's entitlement to claim the priority of the Institutes for BioMedical Research, Inc., 250 Massachusetts earlier application (Rule 4.17(iii)) Avenue, Cambridge, Massachusetts 02139 (US). Published: (72) Inventors; and — with declaration under Article 17(2)(a); without abstract; (71) Applicants (for US only): GRANDA, Brian [US/US]; No¬ title not checked by the International Searching Authority vartis Institutes for BioMedical Research, Inc., 250 Mass¬ — with sequence listing part of description (Rule 5.2(a)) achusetts Avenue, Cambridge, Massachusetts 02139 (US). BLANKENSHIP, John [US/US]; Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, Massachusetts 02139 (US). ABUJOUB, Ai¬ da [US/US]; Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, Massachu¬ setts 02139 (US). FLEMING, Tony [US/US]; Novartis In¬ stitutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, Massachusetts 02139 (US). LU, Hai- hui [US/US]; Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, Massachu¬ setts 02139 (US). HONG, Connie [US/US]; Novartis In¬ stitutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, Massachusetts 02139 (US). HOLM- BERG, Brian [US/US]; Novartis Institutes for BioMed¬ ical Research, Inc., 250 Massachusetts Avenue, Cambridge, Massachusetts 02139 (US). (74) Agent: ABU-SHAAR, Muna et al.; Biospark Intellectual Property Law, 1 Broadway, 14th Floor, Cambridge, Mass¬ achusetts 02142 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, 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, (54) Title: TRISPECIFIC BINDING MOLECULES AGAINST BCMA AND USES THEREOF (57) Abstract: TRISPECIFIC BINDING MOLECULES AGAINST BCMA AND USES THEREOF 1. CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the priority benefit of U.S. provisional application nos. 62/850,889, filed May 2 1, 2019, and 62/854,667, filed May 30, 2019, the contents of both of which are incorporated herein in their entireties by reference thereto. 2. SEQUENCE LISTING [0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on May 13, 2020, is named NOV-005WO_SL.txt and is 595,602 bytes in size. 3. FIELD OF INVENTION [0003] The disclosure generally relates to multispecific binding molecules that engage BCMA, CD3 or other component of a TCR complex on T-cells, and either CD2 or a human tumor- associated antigen (“TAA”), and their use for treating diseases and disorders associated with expression of BCMA. 4. BACKGROUND [0004] BCMA is a tumor necrosis family receptor (TNFR) member expressed on cells of the B- cell lineage. BCMA expression is the highest on terminally differentiated B cells that assume the long lived plasma cell fate, including plasma cells, plasmablasts and a subpopulation of activated B cells and memory B cells. BCMA is involved in mediating the survival of plasma cells for maintaining long-term humoral immunity. The expression of BCMA has been linked to a number of cancers, autoimmune disorders, and infectious diseases. Cancers with increased expression of BCMA include some hematological cancers, such as multiple myeloma, Hodgkin’s and non-Hodgkin’s lymphoma, various leukemias, and glioblastoma. [0005] Redirected targeted T-cell lysis (RTCC) is an exciting mechanism for first line treatment and refractory settings. Antibodies and antibody fragments with their exquisite selectivity have been successfully engineered in a variety of formats to allow for the dual specificities required to cross-link T-cells to a single receptor on the target cell. [0006] There is a need for improved RTCC approaches that target BCMA. 5. SUMMARY [0007] The present disclosure extends the principles of redirected targeted T-cell lysis (RTCC) by providing multispecific binding molecules (“MBMs”) that engage BCMA, CD3 or other component of a T cell receptor (TCR) complex on T-cells, and either CD2 or a human tumor- associated antigen (“TAA”). Without being bound by theory, the inventors believe that combining CD2- and TCR complex-engagement in a single multispecific molecule can stimulate both a primary signaling pathway that promotes T-cell mediated lysis of tumor cells (by clustering TCRs, for example) and a second co-stimulatory pathway to induce T-cell proliferation and potentially overcome anergy. Also without being bound by theory, it is believed that engaging a TAA in addition to BCMA and a component of a TCR complex will improve the clinical outcomes of RTCC therapy of cancer, e.g., B cell malignancies by targeting a greater number of cancerous B cells than using bispecific engagers that target only a BCMA and a TCR complex component. [0008] In one aspect, the present disclosure provides MBMs (e.g., trispecific binding molecules (“TBMs”)) that bind to (1) human BCMA, (2) CD3 or other component of a TCR complex, and (3) CD2. [0009] In another aspect, the present disclosure provides MBMs (e.g., trispecific binding molecules (“TBMs”)) that bind to (1) human BCMA, (2) CD3 or other component of a TCR complex, and (3) a TAA. [0010] The MBMs (e.g., TBMs) comprise at least three antigen-binding modules (“ABMs”) that can bind (i) BCMA (ABM1), (ii) a component of a TCR complex (ABM2), and (iii) either CD2 or a TAA (ABM3). In some embodiments, each antigen-binding module is capable of binding its respective target at the same time as each of the other antigen-binding modules is bound to its respective target. ABM1 is immunoglobulin based, while ABM2 and ABM3 can be immunoglobulin- or non-immunoglobulin-based. Therefore the MBMs (e.g., TBMs) can include immunoglobulin-based ABMs or any combination of immunoglobulin- and non-immunoglobulin- based ABMs. Immunoglobulin-based ABMs that can be used in the MBMs (e.g., TBMs) are described in Section 7.2.1 and specific embodiments 1 to 142, 145 to 741, 782 to 793, 798 to 803, and 833 to 856, infra. Non-immunoglobulin-based ABMs that can be used in the MBMs (e.g., TBMs) are described in Section 7.2.2 and specific embodiments 143 to 144, 743 to 782, and 795 to 797, infra. Further features of exemplary ABMs that bind to human BCMA are described in Section 7.5 and specific embodiments 1 to 142, infra. Further features of exemplary ABMs that bind to a component of a TCR complex are described in Section 7.6 and specific embodiments 151 to 741, infra. Further features of exemplary ABMs that bind to CD2 are described in Section 7.7 and specific embodiments 742 to 793, infra. Further features of exemplary ABMs that bind to TAAs are described in Section 7.8 and specific embodiments 794 to 856, infra. [001 1] The ABMs of a MBM (e.g., TBM) (or portions thereof) can be connected to each other, for example, by short peptide linkers or by an Fc domain. Methods and components for connecting ABMs to form a MBM are described in Section 7.3 and specific embodiments 857 to 1159, infra. [0012] MBMs (e.g ., TBMs) have at least three ABMs (e.g. , a TBM is at least trivalent), but can also have more than three ABMs. For example, a MBM (e.g., a TBM) can have four ABMs (i.e., is tetravalent), five ABMs (i.e., is pentavalent), or six ABMs (i.e., is hexavalent), provided that the MBM has at least one ABM that can bind BCMA, at least one ABM that can bind a component of a TCR complex, and at least one ABM that can bind either CD2 or a TAA. Exemplary trivalent, tetravalent, pentavalent, and hexavalent TBM configurations are shown in FIG. 1 and described in Section 7.4 and specific embodiments 1160 to 1263, infra. [0013] The disclosure further provides nucleic acids encoding the MBMs (either in a single nucleic acid or a plurality of nucleic acids) and recombinant host cells and cell lines engineered to express the nucleic acids and MBMs of the disclosure.
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