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

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. Effects of high‐dose (left) and low‐dose application (right) of TGN1412/TAB08, During the phase I study in 2006, a high dose of the superagonist led to polyclonal activation of regulatory and CD4EM T cells, including the release of proinflammatory cytokines. In contrast, low‐dose application during the second phase I trial selectively activated Treg cells, and is now tested in rheumatoid arthritis patients. Migration to sites of inflammation is extrapolated from rodent studies.