title: A novel anti-CD37 antibody-drug conjugate with multiple anti-tumor mechanisms for the treatment of B-cell malignancies.
abstract: CD37 has gathered renewed interest as a therapeutic target in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL); however, CD37-directed antibody-drug conjugates (ADCs) have not been explored. Here, we identified a novel anti-CD37 antibody, K7153A, with potent in vitro activity against B-cell lines through multiple mechanisms including apoptosis induction, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity. The antibody was conjugated to the maytansinoid, DM1, a potent antimicrotubule agent, via the thioether linker, N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and the resulting ADC, IMGN529, retained the intrinsic antibody activities and showed enhanced cytotoxic activity from targeted payload delivery. In lymphoma cell lines, IMGN529 induced G2/M cell cycle arrest after internalization and lysosomal processing to lysine-N(ε)-SMCC-DM1 as the sole intracellular maytansinoid metabolite. IMGN529 was highly active against subcutaneous B-cell tumor xenografts in severe combined immunodeficient mice with comparable or better activity than rituximab, a combination of cyclophosphamide, vincristine, and prednisone, or bendamustine. In human blood cells, CD37 is expressed in B cells at similar levels as CD20, and IMGN529 resulted in potent and specific depletion of normal and CLL B cells. These results support evaluation of the CD37-targeted ADC, IMGN529, in clinical trials in patients with B-cell malignancies including NHL and CLL.
authors.affiliation: Discovery Research.
authors.forename: Jutta
authors.initials: J
authors.lastname: Deckert
authors.forename: Peter U
authors.initials: PU
authors.lastname: Park
authors.forename: Sharon
authors.initials: S
authors.lastname: Chicklas
authors.forename: Yong
authors.initials: Y
authors.lastname: Yi
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Katharine C
authors.initials: KC
authors.lastname: Lai
authors.forename: Michele F
authors.initials: MF
authors.lastname: Mayo
authors.forename: Christina N
authors.initials: CN
authors.lastname: Carrigan
authors.forename: Hans K
authors.initials: HK
authors.lastname: Erickson
authors.forename: Jan
authors.initials: J
authors.lastname: Pinkas
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lutz
authors.forename: Thomas
authors.initials: T
authors.lastname: Chittenden
authors.forename: John M
authors.initials: JM
authors.lastname: Lambert
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D000069461:Bendamustine Hydrochloride; D045744:Cell Line, Tumor / Q000187:drug effects; D003520:Cyclophosphamide / Q000008:administration & dosage; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009588:Nitrogen Mustard Compounds / Q000627:therapeutic use; D011241:Prednisone / Q000008:administration & dosage; D000069283:Rituximab; D059470:Tetraspanins / Q000276:immunology*; D014750:Vincristine / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000951:Antigens, Neoplasm; C059071:CD37 protein, human; D000922:Immunotoxins; C585626:K7153A; D009588:Nitrogen Mustard Compounds; D059470:Tetraspanins; D008453:Maytansine; D000069283:Rituximab; D014750:Vincristine; D003520:Cyclophosphamide; D000069461:Bendamustine Hydrochloride; D011241:Prednisone; C585625:naratuximab emtansine