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.

Disruption of GAS6/AXL Signaling as a Therapeutic Approach to Treating Cancer

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.

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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.

Media

Cell Wars – Dr. Gail McIntyre, Chief Scientific Officer, Aravive – Researching Ways to Combat Disease at the Cellular Level

Finding Genius Podcast, June 27, 2019

Enough with the me-too drugs. New treatments should be worthy of the people who invest their lives in clinical trials

STAT First Opinion, September 4, 2019

PharmaVOICE100, Commanders and Chiefs | Dr. Gail McIntyre, Delivering Results

PharmaVOICE100, August 2020

White Paper

Novel Approaches Designed to Enhance the Efficacy of Cancer Treatments by Suppressing Mechanisms of Tumor Metastasis and Chemoresistance

Gail McIntyre, Ph.D.

Publications

Webcast: SGO 2020: AVB-S6-500, a receptor tyrosine kinase AXL inhibitor, has improved therapeutic efficacy in combination with bevacizumab in uterine serous cancer mouse model

Presentation by Michael D. Toboni, MD, MPH, PGY-5 Gynecologic Oncology Fellow, Washington University, St. Louis, Dr. Katherine Fuh Lab

Improving response to chemotherapy in HGSOC by inhibiting the GAS6/AXL pathway & inducing a homologous recombination (HR) deficiency

Mary M Mullen, MD, Elena Lomonosova, PhD, Michael Toboni, MD, MPH, Hollie Noia, BS, Daniel Wilke, BS, Alyssa Oplt, BS, Lei Guo, MS, Lindsay M Kuroki MD, Andrea R Hagemann, MD, MSCI, Carolyn K McCourt, MD, Premal H Thaker, MD, MS, David G. Mutch, MD, Matthew A Powell, MD, Katherine C Fuh MD, PhD

Siteman Cancer Center, 28 March 2020.

Improving response to olaparib in uterine serous cancer through treatment with AVB-S6-500, a receptor tyrosine kinase AXL inhibitor

M.D. Toboni, M.M. Mullen, J.I. Tankou, H. Noia, A. Oplt, D. Wilke, P. Cannon, L.M. Kuroki, A.R. Hagemann, C.K. McCourt, P.H. Thaker, D.G. Mutch, M.A. Powell and K.C. Fuh.

Siteman Cancer Center, 4 March 2020.

Target‐Mediated Drug Disposition Pharmacokinetic/Pharmacodynamic Model‐Informed Dose Selection for the First‐in‐Human Study of AVB‐S6‐500

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

ESMO 2019: Phase 1b/2 Study of AVB-500 (High Affinity Inhibitor of GAS6/AXL Path) in Combination with PAC and PLD in Platinum Resistant Recurrent Ovarian Cancer (NCT03639246)

Abstract 6602 Authors: B. Monk, R. Coleman, K. Moore, K. Fuh, L. Bonifacio, G. McIntyre, D. Prohaska, A. Giaccia, M.J. Baker, R. Tabibiazar, M. Bookman

S100A10 is a critical mediator of GAS6/AXL-induced angiogenesis in renal cell carcinoma

Yiren Xiao, Hongjuan Zhao, Lei Tian, Rosalie Nolley, Anh N Diep, Anne Ernst, Katherine C. Fuh, Yu Rebecca Miao, Rie von Eyben, John T. Leppert, James D. Brooks, Donna M. Peehl, Amato J. Giaccia and Erinn B. Rankin.
Cancer Research, 4 October 2019. doi: 10.1158/0008-5472.CAN-19-1366

Therapeutic GAS6/AXL inhibition of tumor and stromal cells increases DNA damage and improves response to chemotherapy in ovarian cancer

Mary M Mullen, MD, Elena Lomonosova, PhD, Hollie Noia, BS, Lei Guo, MS, Lindsay M Kuroki MD, Andrea R Hagemann, MD, MSCI, Carolyn K McCourt, MD, Premal H Thaker, MD, MS, David G. Mutch, MD, Matthew A Powell, MD, Katherine C Fuh MD, PhD

Division of Gynecologic Oncology, Washington University, St. Louis, MO

Expedited Development of AVB-S6 through the use of a Proprietary Biomarker in Healthy Volunteers to Guide Dosing in Oncology Studies

Gail McIntyre, Laura Bonifacio, Dave Prohaska, Jing Shang, Yoshinobu Yokota, Aaron Moss, Amato Giaccia, Michael Dodds, and Ray Tabibiazar

Aravive Biologics, Inc., Houston, TX; SNBL, Everett, WA Certara L, Princeton, NJ; Stanford University, CA

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