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US-12624118-B2 - Trispecific binding molecules against BCMA and uses thereof

US12624118B2US 12624118 B2US12624118 B2US 12624118B2US-12624118-B2

Abstract

The present disclosure provides multispecific binding molecules that specifically bind to BCMA, a component of a human T-cell receptor complex and either CD2 or a tumor associated antigen, conjugates comprising the multispecific binding molecules, and pharmaceutical compositions comprising the multispecific binding molecules and the conjugates. The disclosure further provides methods of using the multispecific binding molecules to treat disease and disorders associated with expression of BCMA. The disclosure yet further provides recombinant host cells engineered to express the multispecific binding molecules and methods of producing the multispecific binding molecules by culturing the host cells under conditions in which the multispecific binding molecules are expressed.

Inventors

  • Brian Walter Granda
  • John Blankenship
  • Aida Abujoub
  • Tony Fleming
  • Lu HUANG
  • Connie HONG
  • Brian HOLMBERG
  • Haihui Lu

Assignees

  • NOVARTIS AG

Dates

Publication Date
20260512
Application Date
20200519

Claims (20)

  1. 1 . A multispecific binding molecule (MBM), comprising: (a) an antigen-binding module 1 (ABM1) that binds specifically to human BCMA and comprises (i) according to the Kabat definition CDR-L1, CDR-L2 and CDR-L3 sequences set forth in SEQ ID NOs: 100, 175, and 183, respectively, and CDR-H1, CDR-H2 and CDR-H3 sequences set forth in SEQ ID NOs: 112, 185, and 122, respectively; (ii) according to the Chothia definition CDR-L1, CDR-L2 and CDR-L3 sequences set forth in SEQ ID NOs: 101, 105, and 209, respectively, and CDR-H1, CDR-H2 and CDR-H3 sequences set forth in SEQ ID NOs: 211, 213, and 122, respectively; or (iii) according to the IMGT definition CDR-L1, CDR-L2 and CDR-L3 sequences set forth in SEQ ID NOs: 102, 105, and 183, respectively, and CDR-H1, CDR-H2 and CDR-H3 sequences set forth in SEQ ID NOs: 235, 238, and 124, respectively; (iv) according to the combined Kabat and Chothia definitions CDR-L1, CDR-L2 and CDR-L3 sequences set forth in SEQ ID NOs: 100, 175, and 183, respectively, and CDR-H1, CDR-H2 and CDR-H3 sequences set forth in SEQ ID NOs: 261, 185, and 122, respectively; (v) according to the combined Kabat and IMGT definitions CDR-L1, CDR-L2 and CDR-L3 sequences set forth in SEQ ID NOs: 100, 175, and 183, respectively, and CDR-H1, CDR-H2 and CDR-H3 sequences set forth in SEQ ID NOs: 261, 185, and 124, respectively; or (vi) according to the combined Chothia and IMGT definitions CDR-L1, CDR-L2 and CDR-L3 sequences set forth in SEQ ID NOs: 101, 105, and 183, respectively, and CDR-H1, CDR-H2 and CDR-H3 sequences set forth in SEQ ID NOs: 235, 238, and 124, respectively; (b) an antigen-binding module 2 (ABM2) that binds specifically to a component of a human T-cell receptor (TCR) complex; and (c) an antigen-binding module 3 (ABM3) that binds specifically to human CD2 or a human tumor-associated antigen (TAA).
  2. 2 . The MBM of claim 1 , wherein ABM1 comprises a light chain variable sequence set forth in SEQ ID NO:273 and a heavy chain variable sequence set forth in SEQ ID NO:297.
  3. 3 . The MBM of claim 1 , wherein ABM1 is an antibody, an antibody fragment, an scFv, a dsFv, a Fv, a Fab, an scFab, or a (Fab′)2.
  4. 4 . The MBM of claim 1 , wherein the component of the TCR complex is CD3.
  5. 5 . The MBM of claim 1 , wherein the component of the TCR complex is TCR-α, TCR-β, a TCR-α/β dimer, TCR-γ, TCR-δ, or a TCR-γ/δ dimer.
  6. 6 . The MBM of claim 1 , wherein ABM3 binds specifically to human CD2.
  7. 7 . The MBM of claim 6 , wherein ABM3 is a non-immunoglobulin scaffold based ABM and comprises a receptor binding domain of a CD2 ligand.
  8. 8 . The MBM of claim 7 , wherein ABM3 is a CD58 moiety.
  9. 9 . The MBM of claim 8 , wherein the CD58 moiety comprises the amino acid sequence as set forth in SEQ ID NO: 515, SEQ ID NO: 516, SEQ ID NO: 517, SEQ ID NO: 518, SEQ ID NO: 519, SEQ ID NO: 520, SEQ ID NO: 521, SEQ ID NO:522, SEQ ID NO: 523, SEQ ID NO:524, or SEQ ID NO:525.
  10. 10 . The MBM of claim 1 , wherein ABM3 binds specifically to a human TAA.
  11. 11 . The MBM of claim 10 , wherein the TAA is selected from CD19, CD20, CD22, CD123, CD33, CLL1, CD138, CS1, CD38, CD133, FLT3, CD52, TNFRSF13C, TNFRSF13B, CXCR4, PD-L1, LY9, CD200, FCGR2B, CD21, CD23, CD24, CD40L, CD72, CD79a, and CD79b.
  12. 12 . The MBM of claim 1 , which comprises an Fc domain.
  13. 13 . The MBM of claim 12 , wherein the Fc domain is an Fc heterodimer.
  14. 14 . A conjugate comprising the MBM of claim 1 , and a therapeutic agent, a diagnostic agent, a masking moiety, a cleavable moiety, or any combination thereof.
  15. 15 . A preparation of MBMs comprising a plurality of MBMs molecules according to claim 1 , wherein the plurality comprises at least 100 conjugate molecules.
  16. 16 . A pharmaceutical composition comprising the MBM of claim 1 , and an excipient.
  17. 17 . A method of treating a subject having an autoimmune disorder associated with expression of BCMA, comprising administering to the subject an effective amount of the MBM of claim 1 , wherein the autoimmune disorder is selected from systemic lupus erythematosus (SLE), Sjögren's syndrome, scleroderma, rheumatoid arthritis (RA), juvenile idiopathic arthritis, graft versus host disease, dermatomyositis, type I diabetes mellitus, Hashimoto's thyroiditis, Graves's disease, Addison's disease, celiac disease, Crohn's Disease, pernicious anaemia, pemphigus vulgaris, vitiligo, autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura, giant cell arteritis, myasthenia gravis, multiple sclerosis (MS), glomerulonephritis, Goodpasture's syndrome, bullous pemphigoid, ulcerative colitis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, anti-phospholipid syndrome, narcolepsy, sarcoidosis, and Wegener's granulomatosis.
  18. 18 . The method of claim 17 , wherein the autoimmune disorder is relapsing-remitting multiple sclerosis (RRMS).
  19. 19 . A method of treating a subject having a BCMA expressing cancer, comprising administering to the subject an effective amount of the MBM of claim 1 .
  20. 20 . The method of claim 19 , wherein the cancer is a B cell malignancy selected from selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma and multiple myeloma.

Description

1. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the priority benefit of U.S. provisional application Nos. 62/850,889, filed May 21, 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 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 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 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. 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. There is a need for improved RTCC approaches that target BCMA. 5. SUMMARY 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. 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. 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. 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. The ABMs of a MBM (e.g., TBM) (or portions thereof) can be connected to each ot