Abstract 71P
Background
CD70 is an attractive tumor target due to its over-expression in numerous solid and hematological cancers and limited expression in healthy cells. In the last decade, multiple anti-CD70 antibody drug conjugates (ADCs) have been developed, but most have been discontinued due to unacceptable toxicity or a narrow therapeutic index. Using an expanded genetic code to create Engineered Precision Biologics, Ambrx has developed ARX305, a CD70-targeted next-generation ADC to potentially overcome the challenges associated with earlier ADCs. ARX305 is comprised of a proprietary, high-affinity, humanized anti-CD70 antibody stably and site-specifically conjugated to AS269, a potent microtubule inhibitor. After binding to CD70 expressed on tumor cells, ARX305 is internalized and catabolized, releasing the cytotoxic payload pAF-AS269 which inhibits cellular proliferation. ARX305 utilizes stable oxime conjugation chemistry, a non-cleavable PEG linker, and a membrane-impermeable payload to minimize premature payload release in circulation and associated off-target toxicity.
Methods
ARX305 was evaluated in multiple pre-clinical pharmacology and toxicology models using standard methodology.
Results
In vitro studies demonstrate that ARX305 selectively induces cytotoxicity of CD70-expressing tumor lines. In multiple in vivo xenograft or disseminated models, ARX305 induced significant tumor growth inhibition or regression whereas unconjugated antibody exhibited poor activity. The stable conjugation and cell-impermeable payload of ARX305 led to high serum stability, a long terminal half-life, and a similar exposure profile as unconjugated antibody in rodent pharmacokinetic studies. Repeat dose studies in cynomolgus monkeys demonstrated ARX305 was tolerated at exposures well above therapeutic exposures in mouse pharmacology studies, indicating a wide therapeutic index.
Conclusions
In summary, the highly selective and potent anti-tumor activity in multiple tumor types and wide pre-clinical therapeutic index of ARX305 support clinical evaluation of this next generation anti-CD70 ADC. ARX305 is currently in a phase 1 dose-escalation study in China.
Clinical trial identification
Editorial acknowledgement
Mark English, PhD, of Cancer Communications and Consultancy Ltd, Cheshire, UK, provided editorial assistance (funded by Ambrx).
Legal entity responsible for the study
Ambrx.
Funding
Ambrx and NovoCodex Biopharmaceuticals.
Disclosure
L. Skidmore: Financial Interests, Institutional, Full or part-time Employment: Ambrx. D. Mills, J.Y. Kim, K. Tatsukawa, N. Knudsen, J. Nelson, J. Wang, S. Zhang: Financial Interests, Personal, Full or part-time Employment: Ambrx.
Resources from the same session
56P - SLC34A2-ROS1 L2026M+G2032R confers resistance to ROS1 tyrosine kinase inhibitors in Ba/F3 cells through a reduced ATP binding pocket volume
Presenter: Christa Dijkhuizen
Session: Poster session 09
57P - Metastasis organotropism: Unveiling associated proteins using network biology
Presenter: Margarida Carrolo
Session: Poster session 09
59P - Correlation of tumor microenvironment signature in advanced stage non-small cell lung cancer with EGFR mutation who received EGFR-TKIs
Presenter: Chaiyapong Ngamchokwathana
Session: Poster session 09
60P - Establishment and characterization of a novel lung adenocarcinoma cell line HX-JCJ harboring MET ex14 skipping mutation
Presenter: Xuejin Ou
Session: Poster session 09
61P - Next generation sequencing and its clinical utility in advanced cancer: Single institute experience from low-middle income country
Presenter: Amit Badola
Session: Poster session 09
62P - Prebiotics modulate gut microbiota-mediated T cell immunity to enhance sintilimab inhibition of lung cancer
Presenter: QIN YAN
Session: Poster session 09
63P - Addition of human chorionic gonadotropin to the current standard mobilization approach with granulocyte-colony stimulating factor increases overall survival in a murine model of peripheral blood stem cell transplantation: Are we far enough for therapy?
Presenter: Andrei Cismaru
Session: Poster session 09
64P - Developing novel therapeutics for bladder cancer leveraging drosophila models
Presenter: Takuya Moriguchi
Session: Poster session 09
65P - Ionizing radiation induces vascular smooth muscle cell senescence through activating NF-κB-CTCF-p16 pathway
Presenter: xuefeng zheng
Session: Poster session 09
66P - Exploring the radiobiology and dosimetry of targeted alpha therapy as a tool to optimize its clinical application: A preclinical study
Presenter: Maria Filomena Botelho
Session: Poster session 09