ARX788, a Site-specific Anti-HER2 Antibody-Drug Conjugate, Demonstrates Potent and Selective Activity in HER2-low and T-DM1-resistant Breast and Gastric Cancers.

Molecular Cancer Therapeutics
Lillian SkidmoreFeng Tian

Abstract

First-generation antibody-drug conjugates (ADC) are heterogeneous mixtures that have shown clinical benefit, but generally exhibited safety issues and a narrow therapeutic window due, in part, to off-target toxicity caused by ADC instability. ARX788 is a next-generation, site-specific anti-HER2 ADC that utilizes a unique nonnatural amino acid-enabled conjugation technology and a noncleavable Amberstatin (AS269) drug-linker to generate a homogeneous ADC with a drug-to-antibody ratio of 1.9. ARX788 exhibits high serum stability in mice and a relatively long ADC half-life of 12.5 days. When compared in vitro against T-DM1 across a panel of cancer cell lines, ARX788 showed superior activity in the lower HER2-expressing cell lines and no activity in normal cardiomyocyte cells. Similarly, ARX788 significantly inhibited tumor growth, and generally outperformed T-DM1 in HER2-high and HER2-low expression xenograft models. Breast and gastric cancer patient-derived xenograft studies confirmed strong antitumor activity of ARX788 in HER2-positive and HER2-low expression tumors, as well as in a T-DM1-resistant model. The encouraging preclinical data support the further development of ARX788 for treatment of patients with HER2-positive breast...Continue Reading

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Citations

Oct 22, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Umbreen HafeezAndrew M Scott
Dec 9, 2020·Molecular Cancer Therapeutics·Philip N MoquistSvetlana O Doronina
Nov 19, 2020·Breast Cancer : Targets and Therapy·Andrea Luque-BolivarMilena Rondón-Lagos
Mar 7, 2021·International Journal of Molecular Sciences·Jinsha LiuSepideh Afshar
Mar 2, 2021·Antibody Therapeutics·Amissi SadikiZhaohui Sunny Zhou
Jul 15, 2021·Journal of Oncology·Aram J AbbasMaher S Saifo
Sep 8, 2021·Cancer Cell International·Reza MahmoudiMohammad Rahmati

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