Triple-specific binding molecules for tumor-associated antigens and their use

Abstract

To provide improved redirected targeted T-cell cytotoxicity approaches.SOLUTION: The present disclosure provides trispecific binding molecules that specifically bind to CD2, CD3 and a tumor-associated antigen, conjugates comprising the trispecific binding molecules, and pharmaceutical compositions comprising the trispecific binding molecules and the conjugates. The disclosure further provides methods of using the trispecific binding molecules to treat cancers that express the tumor-associated antigens. The disclosure yet further provides recombinant host cells engineered to express the trispecific binding molecules and methods of producing the trispecific binding molecules by culturing the host cells under conditions in which the trispecific binding molecules are expressed.SELECTED DRAWING: None

Claims

1. (a) an antigen-binding module 1 (ABM1) comprising (1) a CD58 portion that specifically binds to human CD2 or (2) a CD48 portion that specifically binds to human CD2; (b) an antigen-binding module 2 (ABM2) containing an scFv that specifically binds to CD3; (c) Antigen-binding module 3 (ABM3) containing Fab that specifically binds to human tumor-associated antigens (TAAs) and A triple-specific binding molecule (TBM) containing, A TBM comprising (i) a first semi-antibody containing ABM2, an Fc region, and ABM1 in order from N-terminus to C-terminus, and (ii) a second semi-antibody containing ABM3 and an Fc region in order from N-terminus to C-terminus, wherein the first and second semi-antibodies are associated via the Fc region, and the Fc region forms an Fc domain.

2. The TBM according to claim 1, wherein each antigen-binding module is capable of binding to the respective target of each of the other antigen-binding modules simultaneously.

3. The TBM according to claim 1 or 2, wherein ABM1 is the CD58 portion.

4. The TBM according to claim 3, wherein ABM1 comprises amino acids 30 to 123 of SEQ ID NO:

258.

5. ABM2 is, (a) Any VH and VL pair of CD3-1 to CD3-28 listed in Table 7A; (b) any of the scFv from CD3-21 to CD3-28 listed in Table 7A; (c) A set of six CD-Rs identified for one of the CD3-1 to CD3-128 listed in Table 7B; (d) A set of six CD-Rs specified for any one of CD3-1 to CD3-21 listed in Table 7C; or (e) A set of six CD-Rs, each identified as one of the CD3-1 to CD3-20 listed in Table 7D. A TBM according to any one of claims 1 to 4, including the TBM described in any one of claims 1 to 4.

6. The TBM according to claim 5, wherein ABM2 includes the VH and VL sequences of CD3-21 as described in Table 7A.

7. The TAAs include TSHR, CD171, CS-1, CLL-1, GD3, Tn Ag, FLT3, CD38, CD44v6, B7H3, KIT, IL-13Ra2, IL-11Ra, PSCA, PRSS21, VEGFR2, Lewis Y, CD24, PDGFR-β, SSEA -4, MUC1, EGFR, EGFRvIII, NCAM, CAIX, LMP2, EphA2, fucosyl GM1, sLe, GM3, TGS5, HMWMAA, o-acetyl-GD2, GD2, leaf Acid receptor α, folate receptor β, TEM1 / CD248, TEM7R, CLDN6, GPRC5D, CXORF61, CD97, CD179a, ALK, polysialic acid, PLAC1, GloboH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, OR51E2, TAARP, WT1, ETV6-AML, sperm protein 17, XAGE1, Tie2, MAD-CT-1, MAD-CT-2, Fos-related antigen 1, p53 mutant, hTERT, sarcoma translocation breakpoint, ML-IAP, ERG (TMPRSS2) ETS fusion gene), NA17, PAX3, androgen receptor, cyclin B1, MYCN, RhoC, CYP1B1, BORIS, SART3, PAX5, OY-TES1, LCK, AKAP-4, SSX2, CD79a, CD79b, CD72, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, IGLL1, CD19, CD20, The TBM according to claims 1 to 6, wherein the TBM is CD30, ERBB2, ROR1, FLT3, TAAG72, CD22, CD33, GD2, BCMA, gp100Tn, FAP, tyrosinase, EPCAM, CEA, Igf-I receptor, cadherin 17, CD32b, GPNMB, GPR64, HER3, LRP6, LYPD8, NKG2D, SLC34A2, SLC39A6, SLITRK6, TACSTD2, or EphB2.

8. A conjugate comprising a TBM according to any one of claims 1 to 7 and a cytotoxic agent or a cell proliferation inhibitor.

9. A pharmaceutical composition comprising TBM and an excipient according to any one of claims 1 to 7.

10. A pharmaceutical composition for treating a subject suffering from cancer, comprising an effective amount of TBM according to any one of claims 1 to 7.

11. The aforementioned cancers include HER2+ cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendiceal cancer, astrocytoma, basal cell carcinoma, brain tumor, bile duct cancer, bladder cancer, bone cancer, breast cancer, bronchial tumor, Burkitt lymphoma, cancer of unknown primary origin, cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasm, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma, embryonal tumor, endometrial cancer, Ependymoma, esophageal cancer, nasal neuroblastoma, fibrous histiocytoma, Ewing's sarcoma, eye cancer, germ cell tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic disease, glioma, head and neck cancer, hairy cell leukemia, hepatocellular carcinoma, histiocytic hyperplasia, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip cancer and oral cancer, liver cancer, lobular carcinoma in situ, lung cancer, lymphoma, ma Chloglobulinemia, malignant fibrous histiocytoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic cervical squamous cell carcinoma of unknown primary origin, median duct cancer associated with the NUT gene, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, nasal cavity cancer and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer A pharmaceutical composition according to claim 10, selected from the group consisting of head cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer and ureteral cancer, retinoblastoma, rhabdoid tumor, salivary gland cancer, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, spinal cord tumor, gastric cancer, T-cell lymphoma, teratoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer and Wilms' tumor.

12. One or more nucleic acids encoding a TBM according to any one of claims 1 to 7.

13. A cell comprising one or more nucleic acids as described in claim 12.

14. Cells transfected with one or more expression vectors containing one or more nucleic acid sequences encoding the TBM described in any one of claims 1 to 7, under the control of one or more promoters.

15. A method for producing TBM, (a) Culturing the cells according to claim 13 or 14 under conditions in which the TBM is expressed; (b) Recovering the TBM from the cell culture A method that includes this.

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