title: Glycovariant anti-CD37 monospecific protein therapeutic exhibits enhanced effector cell-mediated cytotoxicity against chronic and acute B cell malignancies.
abstract: TRU-016 is a SMIP(TM) (monospecific protein therapeutic) molecule against the tetraspanin transmembrane family protein CD37 that is currently in Phase 2 trials in Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL). In an attempt to enhance the ADCC function of SMIP-016, the chimeric version of TRU-016, SMIP-016(GV) was engineered with a modification in a glycosylation site in the Fc domain. The wild-type and glycovariant SMIP proteins mediate comparable Type I antibody-like direct cytotoxicity in the presence of anti-human Fc crosslinker and show a similar tyrosine phosphorylation pattern post-treatment. However, NK cells stimulated with the SMIP-016(GV) exhibit enhanced activation and release 3-fold more interferon-γ compared with SMIP-016. SMIP-016(GV) shows enhanced ADCC function against cells expressing CD37 with NK cell effectors derived from both normal and CLL-affected individuals. Enhanced ADCC is observed against CLL cells and is sustained at concentrations of SMIP-016(GV) as low at 5E(-6) µg/mL on cells expressing minimal CD37 antigen. In support of the biological relevance of this, SMIP-016(GV) mediates effective ADCC against primary acute lymphoblastic leukemia (ALL) cells with low surface expression of CD37. Collectively, these data suggest potential use of the novel therapeutic agent SMIP-016(GV) with enhanced effector function for B cell malignancies, including CLL and ALL therapy.
authors.affiliation: Integrated Biomedical Science Graduate Program; The Ohio State University; Columbus, OH USA; Division of Hematology, Department of Internal Medicine; The Ohio State University; Columbus, OH USA.
authors.forename: Sarwish
authors.initials: S
authors.lastname: Rafiq
authors.forename: Anthony
authors.initials: A
authors.lastname: Siadak
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Butchar
authors.forename: Carolyn
authors.initials: C
authors.lastname: Cheney
authors.forename: Gerard
authors.initials: G
authors.lastname: Lozanski
authors.forename: Naduparambil K
authors.initials: NK
authors.lastname: Jacob
authors.forename: Rosa
authors.initials: R
authors.lastname: Lapalombella
authors.forename: Jackie
authors.initials: J
authors.lastname: McGourty
authors.forename: Meghan
authors.initials: M
authors.lastname: Moledor
authors.forename: Richard
authors.initials: R
authors.lastname: Lowe
authors.forename: Ben
authors.initials: B
authors.lastname: Setter
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Jones
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Flynn
authors.forename: Leslie
authors.initials: L
authors.lastname: Andritsos
authors.forename: Steven
authors.initials: S
authors.lastname: Devine
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.forename: David
authors.initials: D
authors.lastname: Jarjoura
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.forename: Paul
authors.initials: P
authors.lastname: Algate
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Natarajan
authors.initials: N
authors.lastname: Muthusamy
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects* / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D016466:CHO Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006031:Glycosylation; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D015202:Protein Engineering / Q000379:methods; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology*; D059470:Tetraspanins / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; C059071:CD37 protein, human; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; C547387:TRU 016; D059470:Tetraspanins
keywords: ALL; CD37; CLL; Protein Therapeutics