Adenosine deaminase acting on RNA (ADAR1) is an RNA-binding protein that modifies double stranded RNA (dsRNA) through deamination of adenosine (A) to inosine (I). ADAR1 is a potent innate immune checkpoint within tumor cells that prevents dsRNA-induced type 1 IFN signaling.
Inhibiting ADAR1 presents two distinct and synergistic therapeutic modes of action. In the first mode of action, activation of innate immune cells by tumor-generated type 1 IFN: ADAR1 inactivation leads to a dramatic increase in tumor secreted type 1 IFN and associated chemokines, resulting in tumor infiltration and cell mediated anti-tumor immunity, even in PD1-resistant in vivo models.1
In the second mode of action, direct tumor cell cytotoxicity, tumor cells with a high type I IFN signaling signature are intrinsically dependent on ADAR1 for survival and proliferation. Inhibition of ADAR1 in tumor cells de-represses PKR activation, leading to protein translation shutdown and tumor cell death, further stimulating innate and adaptive anti-tumor immunity.2
Through dsRNA editing, ADAR1 prevents the recognition of dsRNA by intracellular receptors that stimulate type 1 IFN production and activate an innate immune response. ADAR1 inactivation in tumor cells results in type 1 IFN production and a multi-lineage immune response leading to tumor inflammation and the generation of durable tumor-specific immunity. Importantly, genetic studies have demonstrated that inactivation of ADAR can reverse resistance to anti-PD1 in mouse tumor models, even in the absence of cytotoxic T cell activity.
Using the Silicon Therapeutics computational physics platform, we are developing ADAR1-specific antagonists to treat selected cancer patients identified by proprietary biomarkers that predict therapeutic response to ADAR1 inhibition. In early clinical development we will establish single agent clinical proof-of-concept (POC) in a biomarker-enriched responder patient population and also establish PD1/PDL1 combination activity in patients that are refractory/resistant to immune checkpoint therapy (ICT) alone.
- Ishizuka JJ et al, Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature. 2019 Jan;565(7737):43-48
- Liu H, et al, Tumor-derived IFN triggers chronic pathway agonism and sensitivity to ADAR loss. Nat Med. 2019 Jan;25(1):95-102