Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

Sci Transl Med. 2018 Oct 17;10(463):eaat5775. doi: 10.1126/scitranslmed.aat5775.

Abstract

A primary barrier to the success of T cell-recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, we developed an anti-HER2/CD3 T cell-dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues. Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells. The increased selectivity to HER2-overexpressing cells is expected to mitigate the risk of adverse effects and increase the therapeutic index. Results included in this manuscript not only support the clinical development of anti-HER2/CD3 1Fab-immunoglobulin G TDB but also introduce a potentially widely applicable strategy for other T cell-directed therapies. The potential of this discovery has broad applications to further enable consideration of solid tumor targets that were previously limited by on-target, but off-tumor, autoimmunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Bispecific / immunology
  • Antibody Affinity / immunology*
  • CD3 Complex / immunology*
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic*
  • Humans
  • Immunoglobulin Fab Fragments / metabolism
  • Immunoglobulin G / metabolism
  • Lymphocyte Activation / immunology
  • Protein Binding
  • Receptor, ErbB-2 / immunology*

Substances

  • Antibodies, Bispecific
  • CD3 Complex
  • Immunoglobulin Fab Fragments
  • Immunoglobulin G
  • Receptor, ErbB-2