SL-9258

Here, we evaluated whether in vivo administration of mRNA/LNP formulations of SIRPα-Fc-CD40L and TIGIT-Fc-LIGHT could achieve oligomerization and extend exposure, on-target activity, and anti-tumor responses comparable to that of the corresponding recombinant fusion proteins...Furthermore, the mRNA/LNPs demonstrated improved efficacy in combination with anti-PD-L1 relative to the recombinant fusion proteins. These data support the delivery of complex oligomeric biologics as mRNA/LNP formulations, where high therapeutic expression and exposure could translate into improved patient outcomes.

Importantly, HVEM was more widely expressed than DNAM-1 on T memory stem cells and TILs across a range of tumor types. Taken together, the mechanisms of TIGIT-Fc-LIGHT promoted strong antitumor activity in preclinical tumor models of primary and acquired resistance to PD-1 blockade, suggesting that immune costimulation mediated by LIGHT may broaden the clinical utility of TIGIT blockade.

Conclusions TIGIT-Fc-LIGHT was designed to overcome the limitations of TIGIT blocking antibodies through: 1) preserved costimulation in advanced tumors, 2) direct myeloid cell activation, 3) blockade of all known TIGIT ligands, and with 4) no risk of depleting effector lymphocytes since TIGIT-Fc-LIGHT activity does not require Fc function. Pre-clinical data indicate that these goals were achieved, and further development is warranted.