A novel, native-format bispecific antibody triggering T-cell killing of B-cells is robustly active in mouse tumor models and cynomolgus monkeys

Sci Rep. 2015 Dec 11;5:17943. doi: 10.1038/srep17943.

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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Bispecific / chemistry
  • Antibodies, Bispecific / immunology*
  • Antibodies, Bispecific / isolation & purification
  • Antibodies, Bispecific / pharmacology
  • Antibody-Dependent Cell Cytotoxicity*
  • Antigens, CD20 / immunology
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • CD3 Complex / immunology
  • Cell Line, Tumor
  • Chromatography, Affinity
  • Cytokines / metabolism
  • Cytotoxicity, Immunologic*
  • Disease Models, Animal
  • Female
  • Immunophenotyping
  • Macaca fascicularis
  • Mice
  • Mice, Knockout
  • Mice, SCID
  • Models, Molecular
  • Molecular Sequence Data
  • Neoplasms / immunology*
  • Neoplasms / pathology*
  • Neoplasms / therapy
  • Phenotype
  • Protein Conformation
  • Sequence Alignment
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Tumor Burden / drug effects
  • Tumor Burden / immunology

Substances

  • Antibodies, Bispecific
  • Antigens, CD20
  • CD3 Complex
  • Cytokines