Overcoming the Affinity Barrier
AVB-S6-500 is a GAS6 binding protein and AXL decoy receptor. This novel, high-affinity, soluble, Fc-fusion protein is designed to block the activation of GAS6-AXL signaling. AVB-S6-500 is under clinical development as a targeted therapy against ovarian cancer. Additional clinical trials may involve combining AVB-S6-500 with standard of care in a number of tumor types, which may include renal cell carcinoma, acute myeloid leukemia, triple negative breast cancer and pancreatic 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.
In its recently completed Phase 1 clinical trial with AVB-S6-500, the lead development candidate selected from the AVB-S6 family of proteins, Aravive demonstrated clinical proof-of-mechanism for AVB-S6-500 in neutralizing GAS6. In an analysis of the single ascending dose portion of the study, AVB-S6-500 administration resulted in a dose-dependent decrease in measurable, circulating free GAS6 in serum. Importantly, AVB-S6-500 had a favorable safety profile in this first in human study and in preclinical studies. Aravive is poised to initiate the Phase 1b portion of its first Phase 1b/2 clinical trial in patients with platinum resistant ovarian cancer.
Preclinically, the Company has conducted several proof-of-principle studies and established compelling data demonstrating AVB-S6’s efficacy and tolerability in multiple in vitro studies and in vivo models of cancer. In preclinical models, treatment with AVB-S6 proteins alone and in combination with standard chemotherapy have been associated with anti-tumor effects coupled with excellent tolerability. In fact, there has been no appreciable normal tissue toxicity with treatment of AVB-S6.
AVB-S6-500 has better than 100-fold tighter affinity for GAS6 compared to the natural affinity between the ligand and the receptor, providing high specificity and selectivity for the GAS6-AXL pathway.
AVB-S6-500’s neutralization of GAS6 and inhibition of the GAS6-AXL 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 GAS6-AXL interaction stops the progression of cancer. In solid tumors, GAS6-AXL 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. In AML, other treatments in development have toxicity and low response rates with increased likelihood of developing resistance.