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.
AVB-500 Prevents GAS6 from Binding and Activating AXL Signaling
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.
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.
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.
Aravive’s lead product candidate 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.
AVB-500 Inhibits Metastasis And Tumor Growth
Media
Dr. Gail McIntyre, CEO of Aravive, Shares Insight on AVB-500 and its Potential Against ccRCC
PharmaShots, April 12, 2021
Dr. Gail McIntyre, CEO of Aravive, Discusses the Urgent Need for Improved Therapeutic Approaches to Treat Patients with Ovarian Cancer
Health Professional Radio, December 1, 2020
PharmaVOICE100, Commanders and Chiefs | Dr. Gail McIntyre, Delivering Results
PharmaVOICE100, August 2020
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
Cell Wars – Dr. Gail McIntyre, Chief Scientific Officer, Aravive – Researching Ways to Combat Disease at the Cellular Level
Finding Genius Podcast, June 27, 2019
Publications
GAS6-AXL inhibition by AVB-500 overcomes resistance to paclitaxel in endometrial cancer by decreasing tumor cell glycolysis
Shaina F. Bruce, MD; Tyler Woodard, 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
American Association for Cancer Research Annual Meeting, April 8, 2022
Tumor and Stromal AXL Expression Regulate Ovarian Cancer Metastasis
Mary M. Mullen, MD, Lillian van Biljon, BS, Jeanne Quinn, Molly Greenwade MD, Gregory Opara MD, Hollie Noia, BS, Ian S. Hagemann, MD, PhD, Andrea R. Hagemann, MD, MSCI, Lindsay M. Kuroki, MD, Carolyn K. McCourt, MD, Premal H. Thaker, MD, MS, Matthew A. Powell, MD, David G. Mutch, MD, Dineo Khabele, MD, Katherine C. Fuh, MD, PhD
American Association for Cancer Research Annual Meeting, April 8, 2022
GAS6-AXL inhibition by AVB-500 overcomes resistance to paclitaxel in endometrial cancer by decreasing tumor cell glycolysis
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
Society of Gynecologic Oncology Annual Meeting on Women’s Cancer, March 18, 2022
A Phase 1b Study of AVB-S6-500 in Combination with Cabozantinib In Patients with Advanced Clear Cell Renal Cell Carcinoma Who Received Front-Line Treatment
K. Beckermann, N. Vogelzang, S. Mao, M. Ornstein, N. Shah, H. Hammers, X. Gao, D. McDermott, E. Pennella, H. Yan, V. Esquibel, R. Rangwala, M. Campbell
Society for Immunotherapy of Cancer, November 12, 2021
Phase 1b study of AVB-500 in combination with paclitaxel or pegylated liposomal doxorubicin platinum-resistant recurrent ovarian cancer
Katherine C. Fuh, MD, PhD, Michael A. Bookman, MD, Joyce F. Liu, MD, Robert L. Coleman, MD, Thomas J. Herzog, MD, Premal H. Thaker, MD, Bradley J. Monk, MD, Randy Anderson, PhD, Gail McIntyre, PhD, DABT, Reshma Rangwala, MD, PhD, Kathleen N. Moore, MD
Gynecologic Oncology, August 30, 2021
SGO 2021: Phase 1B Study of GAS6/AXL Inhibitor (AVB-500) in Recurrent, Platinum-resistant Ovarian Carcinoma
Katherine C. Fuh, MD, PhD, Michael A. Bookman, MD, Robert L. Coleman, MD, Thomas J. Herzog MD, Premal H. Thaker, MD, Joyce F. Liu MD, Michelle W. Lane, PhD, Reshma A. Rangwala, MD, PhD, Gail F. McIntyre, PhD, Bradley J. Monk, MD, Kathleen N. Moore, MD
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
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