PD-L1 plays a major role in suppressing the adaptive arm of the immune system. Its expression is induced after an initial immune response and subsequently dampens further immune responses. It is frequently overexpressed by cells within the tumor microenvironment and supports the tumor in evading anti-tumor immune responses. PD-L1 is a recognized tumor target as demonstrated by the clinical success of several antibody-based therapies targeting PD-L1. Secarna has successfully demonstrated in various tumor models the superior anti-tumor activity of PD-L1 ASOs in comparison to PD-L1 antibodies. This is most probably caused by the distinguished pharmacokinetic and pharmacodynamic properties of ASOs.
CD39 is a key component within the adenosine axis that allows a tumor to escape from immune-mediated destruction. Targeting CD39 with ASOs holds several advantages compared with targeting other components. For example, it allows for accumulation of immune-stimulatory extracellular ATP (eATP) and in contrast to small molecule inhibitors of the A2A receptor it also reverses A2A receptor-independent immune suppression.
CHOP plays a critical role in maladaptive ER-stress in different cell types. ASOs are ideal to target CHOP as an intracellular transcription factor which is difficult to target with other approaches.
NLRP3 is part of the NLRP3 inflammasome complex and required for maturation of IL-1β and IL-18. Advantages of targeting NLRP3 with ASOs, as compared to e.g. IL-1β antibodies, are the inhibition of Caspase-1 independent mechanisms and IL-18 secretion as well as the reduced risk of infections (alternative pathways leading to IL-1β secretion remain intact).