Since our companion paper demonstrated that Ipilimumab does not block the B7-CTLA-4 interaction under physiological conditions, the mechanism by which Ipilimumab inactivates CTLA-4 molecules remains to be determined. Consistent with a dominant function of human CTLA-4 in CITE, several recent studies including those of our own have demonstrated a critical role for local depletion of Treg cells in Indoramin D5 the tumor microenvironment. Targeting CTLA-4 has shown remarkable long-term benefit and thus remains a valuable tool for cancer immunotherapy if the irAE can be brought under control. An animal model, which recapitulates clinical irAE and CITE, would be valuable for developing safer CTLA-4-targeting reagents. Here, we report such a model using mice harboring the humanized gene. In this model, the clinically used drug, Ipilimumab, induced severe irAE especially when combined with an anti-PD-1 antibody; whereas another mAb, L3D10, induced comparable CITE with Indoramin D5 very mild irAE under the same conditions. The irAE corresponded to systemic T cell activation and resulted in reduced ratios of regulatory to effector T cells (Treg/Teff) among autoreactive T cells. Using mice that were either homozygous or heterozygous for the human allele, we found that the irAE required bi-allelic engagement, while CITE only required monoallelic engagement. As with the immunological distinction for monoallelic vs bi-allelic engagement, we found that bi-allelic engagement of the knock-in mice showed that the levels of anti-DNA antibodies and cancer rejection parameters do not always correlate with each other.24 In particular, we found that one of the antibodies tested, L3D10, Indoramin D5 conferred strongest CITE but yet induced the lowest levels of anti-DNA antibodies among several mAbs tested. Nevertheless, since the anti-CTLA-4 mAb-induced adverse events are relatively mild in mice, this model failed to recapitulate clinical observations. As such it is of limited value in understanding the pathogenesis of irAE and in identification of safe and effective anti-CTLA-4 mAbs. Moreover, since these studies were performed before clinically used anti-CTLA-4 mAbs were available, it is unclear, whether the principles are relevant to irAE induced by clinical products. In developing a mouse model of irAE, we considered three factors. First, since combination therapy with anti-PD-1 and anti-CTLA-4 is being rapidly expanded into multiple indications, a model that recapitulates the combination therapy would be of great significance for the field. Second, the fact that combination therapy results in SAEs (grades 3 and 4 organ toxicity) in more than 50% of the subjects will make it easier to recapitulate irAE in the mouse model. Third, since the mouse is generally more resistant to irAE, one must search for conditions under which the irAE can be faithfully recapitulated. As the autoimmune phenotype in Indoramin D5 mice occurs at a young age,25,26 and targeted mutation of the gene in adult mice leads to less severe autoimmune disease,27 we reasoned that mice may be most susceptible to anti-CTLA-4 mAbs if they are administrated at a young age. Taking these factors into consideration, we now report a model system that faithfully recapitulates the irAEs observed in clinical trials of combination therapy. More importantly, by using different genetic models and therapeutic anti-CTLA-4 mAbs, we show that irAE and CITE are not intrinsically linked and they have a distinct genetic and immunological basis, as complete CTLA-4 occupation, systemic T cell activation and preferential expansion of self-reactive T cells are dispensable for tumor rejection but correlate with irAE. Moreover, blocking the B7-CTLA-4 interaction impacts neither safety nor efficacy of anti-CTLA-4 Mouse monoclonal to SUZ12 antibodies. Rather, our companion paper demonstrated that FcR-mediated Treg depletion in the tumor microenvironment is necessary and sufficient for tumor rejection. These results provide important insights for the therapeutic development of the next generation of safer and more effective anti-CTLA-4 antibodies. Results Human CTLA4 knock-in mice model faithfully recapitulates irAE of combination therapy A Indoramin D5 major challenge in studying the mechanisms and preventive strategies of irAE in combination therapy is that the mouse tolerates high doses of anti-CTLA-4 mAb without significant AE. We choose two human CTLA-4 mAbs for this study: the clinically used Ipilimumab and L3D10, the most potent among our panel of anti-CTLA-4 mAbs.24,28 When compared in the same model, the two mAbs were comparable in causing.
Since our companion paper demonstrated that Ipilimumab does not block the B7-CTLA-4 interaction under physiological conditions, the mechanism by which Ipilimumab inactivates CTLA-4 molecules remains to be determined
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