title: The rise and fall of the CD28 superagonist TGN1412 and its return as TAB08: a personal account.
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.
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, Germany. huenig@vim.uni-wuerzburg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hünig
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000266:history* / Q000627:therapeutic use / Q000633:toxicity; D018106:CD28 Antigens / Q000819:agonists* / Q000266:history; D017321:Clinical Trials, Phase I as Topic / Q000266:history; D016207:Cytokines / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000266:history; D005858:Germany; D064368:Healthy Volunteers; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D008131:London; D008213:Lymphocyte Activation; D008402:Mass Media / Q000266:history; D051379:Mice; D051381:Rats; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D017211:Treatment Failure
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018106:CD28 Antigens; D016207:Cytokines; C585279:TMIGD2 protein, human; C509303:TGN-1412
keywords: CD28 superagonist; TAB08; TGN1412; cytokine storm; regulatory T cell; therapeutic monoclonal antibody