A novel bispecific antibody format enables simultaneous bivalent and monovalent co-engagement of distinct target antigens

MAbs. Nov-Dec 2011;3(6):546-57. doi: 10.4161/mabs.3.6.18123. Epub 2011 Nov 1.

Abstract

Bispecific antibodies based on full-length antibody structures are more optimal than fragment-based formats because they benefit from the favorable properties of the Fc region. However, the homodimeric nature of Fc effectively imposes bivalent binding on all current full-length bispecific antibodies, an attribute that can result in nonspecific activation of cross-linked receptors. We engineered a novel bispecific format, referred to as mAb-Fv, that utilizes a heterodimeric Fc region to enable monovalent co-engagement of a second target antigen in a full-length context. mAb-Fv constructs co-targeting CD16 and CD3 were expressed and purified as heterodimeric species, bound selectively to their co-target antigens, and mediated potent cytotoxic activity by NK cells and T cells, respectively. The capacity to co-engage distinct target antigens simultaneously with different valencies is an improved feature for bispecific antibodies with promising therapeutic implications.

Publication types

  • Evaluation Study

MeSH terms

  • Animals
  • Antibodies, Bispecific / chemistry
  • Antibodies, Bispecific / genetics
  • Antibodies, Bispecific / immunology*
  • Antibodies, Bispecific / metabolism
  • Antibody-Dependent Cell Cytotoxicity / immunology*
  • CD3 Complex / genetics
  • CD3 Complex / immunology*
  • CD3 Complex / metabolism
  • Dimerization
  • HEK293 Cells
  • Humans
  • Immunoglobulin Fc Fragments / chemistry
  • Immunoglobulin Fc Fragments / genetics
  • Immunoglobulin Fc Fragments / immunology*
  • Immunoglobulin Fc Fragments / metabolism
  • Immunoglobulin Fragments / chemistry
  • Immunoglobulin Fragments / genetics
  • Immunoglobulin Fragments / immunology*
  • Immunoglobulin Fragments / metabolism
  • Killer Cells, Natural / immunology
  • Mice
  • Models, Molecular
  • Protein Engineering / methods
  • Receptors, IgG / genetics
  • Receptors, IgG / immunology*
  • Receptors, IgG / metabolism
  • T-Lymphocytes / immunology

Substances

  • Antibodies, Bispecific
  • CD3 Complex
  • Immunoglobulin Fc Fragments
  • Immunoglobulin Fragments
  • Receptors, IgG
  • immunoglobulin Fv