
Our Science
A number of deadly and difficult-to-treat diseases, including cancer and fibrosis, share common underlying disease biology: overgrowth of abnormal cells, which migrate and invade healthy tissues.
A number of deadly and difficult-to-treat diseases, including cancer and fibrosis, share common underlying disease biology: overgrowth of abnormal cells, which migrate and invade healthy tissues.
A virtual educational program featuring Drs. Joseph Bailes, Katherine Fuh, and Aravive CMO Dr. Reshma Rangwala discussing the need for improved approaches in treating select cancers, the role of the GAS6/AXL pathway – an important driver of cell migration and invasion in cancer – and the promise of GAS6/AXL signaling and AVB-500.
In both cancer and fibrosis, the GAS6/AXL signaling pathway has been validated as an important driver of cell migration and invasion, and high levels of GAS6 have been strongly implicated in disease progression and mortality. Current attempts to target this important pathway have fallen short, causing either undesirable off-target effects in patients or limited efficacy from these therapies’ inability to compete with natural GAS6’s high affinity to AXL. To circumvent these challenges, Aravive is taking the entirely novel approach of targeting the GAS6 ligand, rather than the AXL signaling molecule.
The Problem:
GAS6/AXL signaling is an important driver of cell migration and invasion, and is associated with poor prognosis in cancer and fibrosis, but attempts to target this pathway have fallen short. That is because of the high affinity between the AXL receptor (in green) and its ligand, GAS6 (in blue).
Aravive’s lead product candidate AVB-500 is an ultra-high affinity decoy protein that starves the GAS6/AXL signaling pathway of its signal by capturing circulating and bound GAS6, thereby potentially stopping the activation, migration and invasion of aberrant cells. In studies to date, AVB-500 has demonstrated a favorable safety profile as a potential non-toxic drug that halts disease progression by effectively blocking GAS6/AXL signaling.
Our Solution:
AVB-500 (shown in purple) binds circulating and bound GAS6 to starve AXL of its signal and stop migration and invasion of aberrant cells into healthy tissues.
Prior AXL antibodies have failed to achieve sufficient affinity to disrupt the interaction between AXL and GAS6. Small molecule multi-kinase inhibitors targeting AXL are often associated with significant off target toxicity that limits their utility.
Affinity matters because the natural interaction between the ligand GAS6 and the AXL receptor is quite high (Kd~30 pM), thereby requiring a decoy receptor with a higher affinity that outcompetes the natural binding of GAS6. We are targeting the GAS6/AXL signaling pathway using a Fc-fusion decoy receptor with ultra-high affinity for GAS6.
AVB-500 has better than 200-fold tighter affinity for GAS6 compared to the natural affinity of the ligand and the receptor, providing high specificity and selectivity for the AXL/GAS6 pathway.
Activation of the GAS6/AXL signaling pathway causes tumor invasion and metastasis, and high levels of GAS6 and AXL have been strongly associated with drug resistance, rapid disease progression, and lower survival. Current attempts to target this important pathway have fallen short, causing either undesirable off-target effects or limited efficacy. To circumvent these challenges, Aravive is taking the entirely novel approach of targeting the GAS6 ligand, rather than the AXL protein.
Batiraxcept (formerly AVB-500) is an ultra-high affinity decoy protein that captures GAS6, thereby potentially stopping the migration and invasion of tumor cells into healthy tissue. In preclinical studies, batiraxcept has been shown to suppress serum GAS6 to undetectable levels and correspondingly decrease metastatic disease.
In clinical studies to date, batiraxcept has demonstrated a favorable safety profile and compelling early clinical activity in cancer patients. Batiraxcept’s impressive safety and tolerability profile suggests it could be ideal for use in combination with many anti-cancer drugs or as a maintenance therapy. Our proprietary biomarker is supporting development of batiraxcept in multiple oncology indications.
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American Association for Cancer Research Annual Meeting, April 8, 2022
Shaina F. Bruce, MD; Kevin Cho, PhD; Hollie Noia, BS; Elena Lomonosova, PhD; Elizabeth Stock, MD; Alyssa Oplt, BS; Barbara Blachut, MD; Mary M. Mullen, MD; Lindsay M. Kuroki, MD; Andrea R. Hagemann, MD; Carolyn K. McCourt, MD; Premal H. Thaker, MD; Dineo Khabele, MD, Matthew A. Powell, MD; David G. Mutch, MD; Leah P. Shriver PhD; Gary J. Patti PhD; and Katherine C. Fuh, MD, PhD
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Siteman Cancer Center, 4 March 2020.
Laura Bonifacio, Michael Dodds, David Prohaska, Aaron Moss, Amato Giaccia, Ray Tabibiazar and Gail McIntyre.
Clinical and Translational Science, 10 October 2019. doi: 10.1111/cts.12706
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