CD28 Superagonist TGN1412 Research Articles

Revisiting CD28 Superagonist TGN1412 as Potential Therapeutic for Pediatric B Cell Leukemia: A Review.

Pediatric acute lymphoblastic leukemia (ALL) represents the most common pediatric cancer diagnosis, with numbers rising gradually every year. This paper proposes a novel therapeutic agent for pediatric ALL on the basis of a failed clinical drug trial in 2006. TGN1412 was a promising therapeutic agent that yielded outstanding results in both in vitro studies and animal trials. It is a CD28 superagonist monoclonal antibody that activates T regulatory (TReg) cells in the absence of costimulation of the T cell receptor (TCR) by an antigen-presenting cell. This drug was intended as a solution to T cell deficient diseases such as B cell leukemia and autoimmune diseases such as rheumatoid arthritis. When phase I clinical trials were conducted, all volunteers that received the drug experienced severe cytokine release syndrome (CRS) and faced multiple-organ failure within hours. TGN1412 was reassessed and re-entered clinical trials as a therapeutic for rheumatoid arthritis. A new assay was developed to better quantify T cell response, and volunteers in this trial experienced no pro-inflammatory cytokine release. This essay analyzes how misinformation contributed to the failure of TGN1412 in clinical trials and how revisiting this therapeutic could yield a novel treatment for pediatric B cell leukemia.

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.

CD28 co-stimulation in T-cell homeostasis: a recent perspective.

T-cells play a key role within the adaptive immune system mediating cellular immunity and orchestrating the immune response as a whole. Their activation requires not only recognition of antigen/major histocompatibility complexes by the T-cell receptor but in addition co-stimulation via the CD28 molecule through binding to CD80, CD86, or as recently discovered, inducible co-stimulator ligand expressed by antigen-presenting cells. Apart from tight control of the co-stimulatory signal by the T-cell receptor complex, expression of the inhibitory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) sharing its ligands with CD28 is required to avoid inappropriate or prolonged T-cell activation. CD4+ Foxp3+ regulatory T (Treg) cells, which are crucial inhibitors of autoimmunity, add another level of complexity in that they differ from conventional non-regulatory CD4+ T-cells by strongly depending on CD28 signaling for their generation and homeostasis. Moreover, CTLA-4 is constitutively expressed by Treg cells where it serves as a key mediator of suppression, while conventional CD4+ T-cells express CTLA-4 only after activation. Here, we discuss recent insights into the molecular events underlying CD28-mediated co-stimulation, its impact on gene regulation, and the differential role of CD28 expression on Treg cells versus conventional CD4+ and CD8+ T-cells. Moreover, we summarize the exciting therapeutic options which have arisen from our current understanding of T-cell co-stimulation. Some of these have already been translated into the clinic, while others are expected to follow soon due to promising preclinical results. In particular, we discuss the failed 2006 trial of the CD28 superagonist TGN1412, and the return of this potent T-cell activator to clinical development.

Erratum: Storm forecasting: additional lessons from the CD28 superagonist TGN1412 trial

Nature Reviews Immunology 31 Aug 2012 (doi:10.1038/nri3192-c1) On page 2 of the original Correspondence article, under the subheading “Failure to reconcile discordant preclinical data”, the dose of 5.11A1 administered to HIS mice in the study by Legrand et al. was incorrectly stated as 0.3 mg per kg, when it should have been 0.

Storm forecasting: additional lessons from the CD28 superagonist TGN1412 trial

Nature Reviews Immunology 31 Aug 2012 (doi:10.1038/nri3192-c1) On page 2 of the original Correspondence article, under the subheading “Failure to reconcile discordant preclinical data”, the dose of 5.11A1 administered to HIS mice in the study by Legrand et al. was incorrectly stated as 0.3 mg per kg, when it should have been 0.

Response to 'Storm forecasting: additional lessons from the CD28 superagonist TGN1412 trial'

Response to 'Storm forecasting: additional lessons from the CD28 superagonist TGN1412 trial'

The storm has cleared: lessons from the CD28 superagonist TGN1412 trial

The life-threatening cytokine-release syndrome suffered by six volunteers in a Phase I clinical trial following administration of the CD28 superagonist antibody TGN1412 (developed by TeGenero) in March 2006 was completely unpredicted by the preclinical studies. Here, Thomas Hünig, main founder of TeGenero, describes the recent investigations into what went wrong and discusses the lessons learnt for future clinical trials.

Preculture of PBMCs at high cell density increases sensitivity of T-cell responses, revealing cytokine release by CD28 superagonist TGN1412

AbstractHuman volunteers receiving TGN1412, a humanized CD28-specific monoclonal antibody, experienced a life-threatening cytokine release syndrome during a recent trial. Preclinical tests using human PBMCs had failed to announce the rapid release of TNF, IFN-γ, and other toxic cytokines in response to this CD28 “superagonist” (CD28SA). CD28SA activate T-lymphocytes by ligating CD28 without overt engagement of the TCR. They do, however, depend on “tonic” TCR signals, which they amplify. Here we show that short-term preculture of PBMCs at high, but not at low, cell density results in massive cytokine release during subsequent stimulation with soluble TGN1412. Restoration of reactivity was cell-contact dependent, involved functional maturation of both monocytes and T cells, was sensitive to blockade by HLA-specific mAb, and was associated with TCR polarization and tyrosine phosphorylation. CD4 effector memory T cells were identified as the main source of proinflammatory cytokines. Importantly, responses to other T-cell activating agents, including microbial antigens, were also enhanced if PBMCs were first allowed to interact under tissue-like conditions. We provide a protocol, which strongly improves reactivity of circulating T cells to soluble stimulants, thereby allowing for more reliable preclinical testing of both activating and inhibitory immunomodulatory drugs.

Signaling signatures and functional properties of anti-human CD28 superagonistic antibodies.

Superagonistic CD28 antibodies (CD28SAs) activate T lymphocytes without concomitant perturbation of the TCR/CD3-complex. In rodents these reagents induce the preferential expansion of regulatory T cells and can be used for the treatment of autoimmune diseases. Unexpectedly, the humanized CD28 superagonist TGN1412 caused severe and life threatening adverse effects during a recently conducted phase I clinical trail. The underlying molecular mechanisms are as yet unclear. We show that TGN1412 as well as the commercially available CD28 superagonist ANC28.1 induce a delayed but extremely sustained calcium response in human naïve and memory CD4+ T cells but not in cynomolgus T lymphocytes. The sustained Ca++-signal was associated with the activation of multiple intracellular signaling pathways and together these events culminated in the rapid de novo synthesis of high amounts of pro-inflammatory cytokines, most notably IFN-γ and TNF-α. Importantly, sustained transmembranous calcium flux, activation of Src-kinases as well as activation of PI3K were found to be absolutely required for CD28SA-mediated production of IFN-γ and IL-2. Collectively, our data suggest a molecular basis for the severe side effects caused by TGN1412 and impinge upon the relevance of non-human primates as preclinical models for reagents that are supposed to modify the function of human T cells.