The rise and fall of the CD28 superagonist TGN1412 and its return as TAB08: a personal account

FEBS J. 2016 Sep;283(18):3325-34. doi: 10.1111/febs.13754. Epub 2016 Jun 6.

Abstract

Two decades ago, we discovered 'superagonistic' monoclonal antibodies specific for the CD28 molecule which are able to polyclonally activate T cells, in particular regulatory T cells, and are therapeutically active in many rodent models of autoimmunity, inflammation, transplantation, and tissue repair. A phase I trial of the human CD28 superagonist TGN1412 failed in 2006 due to an unexpected cytokine release syndrome, but after it became clear that dose-reduction allows to preferentially address regulatory T cells also in humans, clinical development was resumed under the name TAB08. Here, I recount the story of CD28 superagonist development from a personal perspective with an emphasis on the dramatic events during and after the 2006 phase I trial, the reasons for the failure of preclinical research to warn of the impending cytokine storm, and on the research which allowed resumption of clinical development.

Keywords: CD28 superagonist; TAB08; TGN1412; cytokine storm; regulatory T cell; therapeutic monoclonal antibody.

Publication types

  • Autobiography
  • Historical Article

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / history*
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antibodies, Monoclonal, Humanized / toxicity
  • CD28 Antigens / agonists*
  • CD28 Antigens / history
  • Clinical Trials, Phase I as Topic / history
  • Cytokines / metabolism
  • Drug Evaluation, Preclinical / history
  • Germany
  • Healthy Volunteers
  • History, 20th Century
  • History, 21st Century
  • Humans
  • London
  • Lymphocyte Activation
  • Mass Media / history
  • Mice
  • Rats
  • T-Lymphocytes, Regulatory / immunology
  • Treatment Failure

Substances

  • Antibodies, Monoclonal, Humanized
  • CD28 Antigens
  • Cytokines
  • TMIGD2 protein, human
  • TGN-1412

Personal name as subject

  • Thomas Hunig