AGI-134, a fully synthetic α-Gal-based cancer immunotherapy: Synergy with an anti-PD-1 antibody and pre-clinical pharmacokinetic and toxicity profiles.

Abstract

3083Background: Unlike virtually all non-primate mammals, humans lack α-Gal (Gal-α-1,3-Gal-β-1,4-GlcNAc) epitopes and produce antibodies against α-Gal-positive antigens. Anti-α-Gal (anti-Gal) antibodies are among the most abundant antibodies in humans and responsible for hyper-acute rejection of α-Gal-positive xenotransplants. Studies using rabbit-derived α-Gal glycolipids provided a preclinical proof of principle for α-Gal glycolipids as cancer immunotherapy, inducing a CD8+ T cell response to tumor associated antigens (TAAs) that correlated with protection from distal tumor growth in mice. In the current study we show that a fully synthetic, α-Gal glycolipid-like small molecule, AGI-134, displays potent anti-tumor activity by engaging the cellular and humoral immune system against TAAs. Methods: in vitro and in vivo studies. Results: AGI-134 inserts into the plasma membranes of mouse and human cancer cells in vitro. Anti-Gal IgM and IgG bind to the α-Gal labeled cancer cells and mediate an anti-cancer c...