title: A novel, native-format bispecific antibody triggering T-cell killing of B-cells is robustly active in mouse tumor models and cynomolgus monkeys.
abstract: Bispecific antibodies, while showing great therapeutic potential, pose formidable challenges with respect to their assembly, stability, immunogenicity, and pharmacodynamics. Here we describe a novel class of bispecific antibodies with native human immunoglobulin format. The design exploits differences in the affinities of the immunoglobulin isotypes for Protein A, allowing efficient large-scale purification. Using this format, we generated a bispecific antibody, REGN1979, targeting the B cell marker, CD20, and the CD3 component of the T cell receptor, which triggers redirected killing of B cells. In mice, this antibody prevented growth of B cell tumors and also caused regression of large established tumors. In cynomolgus monkeys, low doses of REGN1979 caused prolonged depletion of B cells in peripheral blood with a serum half-life of approximately 14 days. Further, the antibody induced a deeper depletion of B cells in lymphoid organs than rituximab. This format has broad applicability for development of clinical bispecific antibodies.
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Smith
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: Kara
authors.initials: K
authors.lastname: Olson
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: Lauric J
authors.initials: LJ
authors.lastname: Haber
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: Bindu
authors.initials: B
authors.lastname: Varghese
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: Paurene
authors.initials: P
authors.lastname: Duramad
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Tustian
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: Adelekan
authors.initials: A
authors.lastname: Oyejide
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Kirshner
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: Lauren
authors.initials: L
authors.lastname: Canova
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: Jayanthi
authors.initials: J
authors.lastname: Menon
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Principio
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: Douglas
authors.initials: D
authors.lastname: MacDonald
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: Joel
authors.initials: J
authors.lastname: Kantrowitz
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Papadopoulos
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: Neil
authors.initials: N
authors.lastname: Stahl
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, New York 10591.
authors.forename: Samuel
authors.initials: S
authors.lastname: Davis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018033:Antibodies, Bispecific / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20 / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology; D045744:Cell Line, Tumor; D002846:Chromatography, Affinity; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005260:Female; D016130:Immunophenotyping; D008252:Macaca fascicularis; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D010641:Phenotype; D011487:Protein Conformation; D016415:Sequence Alignment; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology
chemical_list: D018033:Antibodies, Bispecific; D018951:Antigens, CD20; D017252:CD3 Complex; D016207:Cytokines