Overcoming the Affinity Barrier
Aravive-S6 is a first in its class engineered decoy soluble AXL receptor under development for targeted therapy against acute myeloid leukemia (AML) and certain advanced solid tumor indications, including ovarian and breast cancer. This GAS6-binding protein therapeutic, which is a fusion of the extracellular domain of AXL (the receptor for GAS6) with a human IgG1 Fc domain, is designed to bind GAS6 with low femtomolar range affinity and reduce or eliminate its ability to stimulate the AXL pathway. The novel Fc-fusion protein drug candidate neutralizes GAS6 and effectively turns off AXL signaling in tumor cells in preclinical studies.
We have conducted several preclinical proof-of-principle studies and established compelling data demonstrating Aravive-S6’s efficacy and tolerability in multiple in vitro studies and in vivo models of cancer. In preclinical models of AML, treatment with Aravive-S6 alone and in combination with standard chemotherapy has been associated with anti-tumor effects coupled with excellent tolerability. In fact, there has been no appreciable normal tissue toxicity with treatment of Aravive-S6. Aravive has also developed a proprietary complementary diagnostic assay for the measurement of free and total GAS6 levels, which may enable the identification of patients who could preferentially benefit from therapy with Aravive-S6.
Aravive-S6 has better than 100-fold tighter affinity for GAS6 compared to the natural affinity between the ligand and the receptor, providing remarkable high specificity and selectivity for the AXL/GAS6 pathway that no other anti-AXL and anti-GAS6 inhibitors have been reported to match.
Aravive-S6’s neutralization of GAS6 and inhibition of the AXL-GAS6 pathway offers the potential for a novel, targeted therapeutic approach that may be used alone with low toxicity or in combination with other standard-of-care anti-cancer agents.
In both laboratory and animal experiments, inhibition of the AXL-GAS6 interaction stops the progression of AML and other advanced solid tumors. In AML, other treatments in development have toxicity and low response rates with increased likelihood of developing resistance. In solid tumors, AXL/GAS6 inhibition has been shown to have dual anti-cancer effects, including direct anti-tumor effects on survival, invasion, and chemoresistance, and indirect anti-tumor effects via stimulating innate anti-cancer immunity, given the GAS6 role as an innate immunity checkpoint.