LAUSR

ABSTRACT A major complication with enzyme replacement therapy of Factor VIII (FVIII) in Hemophilia A (HA) is the development of anti‐drug antibodies. Recently, we have shown that FVIII administration in the presence of heterogeneous phosphatidylserine (PS) nanoparticles derived from a natural source induces tolerance to FVIII, suggesting that PS converts an immunogen to a tolerogen. However, the specific structural features responsible for the immune‐regulatory properties of PS is unclear. Identifying a specific PS species that is responsible is critical in order to further develop and optimize this nanoparticle. Further, clinical development of this lipid‐based strategy requires optimization of the lipid particle that is homogeneous and synthetic. Here, we investigate the ability of mono‐acylated Lyso‐PS to induce hypo‐responsiveness towards FVIII in HA mice. Administration of both PS and Lyso‐PS FVIII significantly reduced anti‐FVIII antibody responses despite rechallenge with FVIII. Additionally, the Lyso‐PS‐mediated effect was shown to be antigen‐specific as mice responded normally against a rechallenge with an unrelated antigen, ovalbumin. Furthermore, the hypo‐responsiveness observed with Lyso‐PS may involve interactions with a specific PS receptor, TIM‐4, along with increasing regulatory T‐cells. These data indicate that using Lyso‐PS allows for a more homogenous formulation in order to induce tolerance towards therapeutic proteins.