Abstract Text: P-selectin glycoprotein ligand 1 (PSGL-1), which has been described as an adhesion molecule, was recently discovered to be a novel immune checkpoint regulator that modulates T cell homeostasis. Here we show that PSGL-1 is upregulated in activated T cells compared to naïve T cells. Cross-linking of ALTB-168 (neihulizumab, an anti-PSGL-1 agonistic antibody) down regulates early T-cell receptor mediated signaling, T cell proliferation, and cytokine secretion. This inhibitory function is independent of the migration function of PSGL-1 as the binding of P-selectin to PSGL-1 is not interfered by ALTB-168. In a pre-clinical GVHD model, ALTB-168 treatment resulted in increased population of apoptotic CD3 T cells, reduced severity of GVHD and prolonged survival of the mice. In a trans-vivo delayed type hypersensitivity (DTH) study where human PBMC, previously sensitized with tetanus toxoid (TT), was implanted in the mouse footpad together with TT, the induration of the mouse footpad was reduced by ALTB-168 in a dose-dependent manner. DTH studies performed in non-human primate (NHP) also showed that ALTB-168 inhibited skin induration as well as the inflammation of the lesion site. Intriguingly, ALTB-168 treatment does not impact the development of T-cell dependent antibody production, suggesting a marginal impact in primary T cells - a significant safety advantage in clinical development. Indeed, no significant adverse events have been reported for ALTB-168, in which nearly 200 subjects were treated. These data support the continued development of ALTB-168, the first anti-PSGL-1 agonistic antibody that down regulates T cell effector function, for the treatment of human inflammatory diseases.
