The multi-Siglec inhibitor AL009 reprograms suppressive macrophages and activates innate and adaptive tumor immunity

Abstract

AbstractSialic acid–binding immunoglobulin-type lectins (Siglecs) are cell surface receptors that regulate innate and adaptive immunity, with inhibitory Siglecs promoting immune tolerance. In the tumor microenvironment, overexpression of sialic acid glycans exploits inhibitory Siglec signaling, leading to a cancer-permissive phenotype. AL009 is an engineered Siglec-9-Fc fusion molecule that functions as a sialic acid trap and reprograms suppressive macrophages to activate an anti-tumor immune response. AL009 treatment of human myeloid-derived suppressor cells, an in vitro model of tumor-associated macrophages, resulted in an increase in proinflammatory cytokines and chemokines, changes in cell surface markers, and potent relief of T cell inhibition in a co-culture assay. In syngeneic mouse (Mus musculus) tumor models, AL009 engineered with a mouse Fc (AL009m) reduced tumor growth as a monotherapy and in combination with the checkpoint inhibitor anti-PD-L1. In addition, AL009m synergized with the tumor-targeting therapy anti-TRP1 to reduce lung nodules in the B16-F10 intravenous model. Pharmacodynamic marker analysis in syngeneic and humanized mouse tumor models supported an AL009 mechanism of action based on reprogramming tumor-associated macrophages and enhanced T cell activation. Future clinical studies are warranted to further elucidate the safety and efficacy of AL009.