Immunometabolic Pathways

Landos has applied its LANCE platform, focused on immunity and metabolism, to identify important new molecular targets. Through advanced computational modeling-based predictions of immune cell differentiation, tissue-level cellular interactions and molecular signaling cascades, Landos has projected the ability of key targets, LANCL2, NLRX1 and PLXDC2, to address multiple disorders linked to immune function.

The LANCL2 (Lanthionine Synthetase C-Like 2) pathway is a surface membrane-associated receptor that is responsible for modulating key cellular and molecular genes tied to autoimmune disease. Specifically, LANCL2 activation leads to a decrease of inflammation-promoting TNF-alpha, INF-gamma, IL-6 and MCP1 and an increase in regulatory T regulatory cell anti-inflammatory activities. With robust control of both immune and metabolic signaling, Landos believes the novel LANCL2 pathway is relevant in a wide range of autoimmune, inflammatory and metabolic diseases. The Company has prioritized inflammatory bowel disease as its first indication in the LANCL2 pathway due to the significant unmet clinical need and major therapeutic gaps in both UC and CD.

NLR

The NLR (nucleotide-binding domain, leucine rich containing) family of proteins contributes to the regulation of innate and adaptive immunity. Landos has identified NLRX1 as a mitochondria-associated receptor, which serves to control and negatively regulate many of the processes induced by inflammasome activation. The effects of NLRX1 activation include decreased differentiation of effector CD4+ T cells and increased mitochondrial metabolism in immune cells. Furthermore, NLRX1 activation decreases NF-kappa B activity and a wide range of cytokines, including CD4+ T cells and those of myeloid origin.

PLXDC2 Pathway

The PLXDC2 pathway is a transmembrane receptor associated with immunoregulatory functions. Immunologically, PLXDC2 activation leads to the production of IL-10 and prevention of oxidative stress. PLXDC2 intercepts the receptor for advanced glycation end-products (RAGE) signaling pathway. This leads to downstream inhibition of NF-kappa B and HIF-1-alpha signaling that is associated with TNF-alpha, IL-6, MCP1 and other cytokines. Further supporting this anti-inflammatory cascade is an inhibition of the semaphorin 4A/plexin B1 axis that regulates MAPK activation. Through proteolysis of the VEGF receptor, activation of PLXDC2 can also induce anti-angiogenic effects that can limit immune cell infiltration and defects in tissue vascularization and anti-fibrotic effects that can reduce the production of fibronectin.