Tu114 - ALTB-268, a PSGL-1 Agonist Antibody, Ameliorated the Disease Severity in a Murine Model of Colitis and a Human-Mouse Xeno GVHD Model by Down-regulating T Effector Functions

Abstract Text: Agonism of immune checkpoint regulators for the treatment of autoimmune and inflammatory diseases has high potential to become the next wave of immunotherapy. P-selectin glycoprotein ligand 1 (PSGL-1) is now known to function as an immune checkpoint regulator in T cells, in addition to its conventional role as an adhesion molecule involved in leukocyte trafficking. ALTB-268 is an immune checkpoint enhancer (ICE) that agonizes PSGL-1’s regulatory role in T cell functions. In vitro studies showed ALTB-268 down regulates T cell activation, resulting in reduced upregulation of activation markers, diminished T cell proliferation and reduced secretion of inflammatory cytokines. The therapeutic potential of ALTB-268 agonism was evaluated in a humanized mouse model of xenogeneic GVHD (xGVHD) and a human PSGL-1 knock-in mouse model of DSS-induced colitis.
In the human-mouse model of xGVHD, ALTB-268 improved animal survival, reduced GVHD severity score, and reduced human CD4+, CD8+ cells with increased 7-AAD+ apoptotic T cells in the spleen of the ALTB-268 treatment group compared to isotype control. In the DSS-induced colitis model developed in human PSGL-1 KI mice, ALTB-268 ameliorated Disease Activity Index (DAI), reduced inflammatory cell infiltration in colon, and reduced TNFα and IFN-γ levels compared to isotype control.
These results demonstrate the potential of Immune checkpoint enhancers (ICEs) in the treatment of autoimmune or inflammatory diseases and support the clinical development of ALTB-268 in T cell-mediated autoimmune and inflammatory diseases such as ulcerative colitis (UC) and GVHD. ALTB-268 is currently in an ongoing phase 2a study in UC (NCT06109441).