Our Approach
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.
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.
Affinity Matters
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.
Publications
Molecular Pathways: Oncologic Pathways and Their Role in T-cell Exclusion and Immune Evasion – A New Role for the AXL Receptor Tyrosine Kinase
Todd A. Aguilera and Amato J. Giaccia.
DOI: 10.1158/1078-0432.CCR-17-0189 Published January 2017
Targeting GAS6 in cancer, fibrosis and viral infection
Rebecca Miao, Amato Giaccia (Stanford University) and Raymond Tabibiazar (Aravive, Inc.).
Drug Target Review, 9 March 2017. Issue #1, 2017.
Axl Mediates ZIKA Virus Entry in Human Glial Cells and Modulates Innate Immune Responses
Laurent Meertens, Athena Labeau, Ophelie Dejarnac, Sara Cipriani, Laura Sinigaglia, Lucie Bonnet-Madin, Tifenn Le Charpentier, Mohamed Lamine Hafirassou, Alessia Zamborlini, Van-Mai Cao-Lormeau, Muriel Coulpier, Dorothée Missé, Nolwenn Jouvenet, Ray Tabibiazar, Pierre Gressens, Olivier Schwartz, Ali Amara.
DOI: http://dx.doi.org/10.1016/j.celrep.2016.12.045
Reprogramming the immunological microenvironment through radiation and targeting Axl
Aguilera TA, Rafat M, Castellini L, Shehade H, Kariolis MS, Hui AB, Stehr H, von Eyben R, Jiang D, Ellies LG, Koong AC, Diehn M, Rankin EB, Graves EE, Giaccia AJ.
Nat Commun. 2016 Dec 23;7:13898. doi: 10.1038/ncomms13898.
Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies
Kariolis MS, Miao YR, Diep A, Nash SE, Olcina MM, Jiang D, Jones DS 2nd, Kapur S, Mathews II, Koong AC, Rankin EB, Cochran JR, Giaccia AJ.
J Clin Invest. 2016 Nov 28. [Epub ahead of print]
PMID: 27893463
The Receptor Tyrosine Kinase AXL in Cancer Progression
Rankin EB, Giaccia AJ.
Cancers (Basel). 2016 Nov 9;8(11).
PMID: 27834845
Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma
Zhou L, Liu XD, Sun M, Zhang X, German P, Bai S, Ding Z, Tannir N, Wood CG, Matin SF, Karam JA, Tamboli P, Sircar K, Rao P, Rankin EB, Laird DA, Hoang AG, Walker CL, Giaccia AJ, Jonasch E.
Oncogene. 2016 May;35(21):2687-97.
PMID: 26364599
An engineered Axl ‘decoy receptor’ effectively silences the Gas6-Axl signaling axis
Kariolis MS, Miao YR, Jones DS 2nd, Kapur S, Mathews II, Giaccia AJ, Cochran JR.
Nat Chem Biol. 2014 Nov;10(11):977-83.
PMID: 25242553
Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET
Rankin EB, Fuh KC, Castellini L, Viswanathan K, Finger EC, Diep AN, LaGory EL, Kariolis MS, Chan A, Lindgren D, Axelson H, Miao YR, Krieg AJ, Giaccia AJ.
Proc Natl Acad Sci U S A. 2014 Sep 16;111(37):13373-8.
PMID: 25187556
AXL is an essential factor and therapeutic target for metastatic ovarian cancer
Rankin EB, Fuh KC, Taylor TE, Krieg AJ, Musser M, Yuan J, Wei K, Kuo CJ, Longacre TA, Giaccia AJ.
Cancer Res. 2010 Oct 1;70(19):7570-9.
PMID: 20858715