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Ref Type Journal Article
PMID (32669315)
Authors Skidmore L, Sakamuri S, Knudsen NA, Hewet AG, Milutinovic S, Barkho W, Biroc SL, Kirtley J, Marsden R, Storey K, Lopez I, Yu W, Fang SY, Yao S, Gu Y, Tian F
Title 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.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 19 9 2020 Sep 1833-1843 Mol Cancer Ther
URL
Abstract Text 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 and gastric cancer, including those who have developed T-DM1 resistance, and patients with HER2-low expression tumors who are currently ineligible to receive HER2-targeted therapy.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
ARX-788 ARX-788 0 4
Drug Name Trade Name Synonyms Drug Classes Drug Description
ARX-788 ARX788|ARX 788 HER2 (ERBB2) Antibody 72 HER2 (ERBB2) Antibody-Drug Conjugate 27 ARX-788 is an antibody-drug conjugate (ADC) comprising a dolastatin analog and an antibody specific to ERBB2 (HER2), which may result in cell death and tumor regression (Cancer Res 2015;75(15 Suppl):Abstract nr 639, PMID: 30841523, PMID: 32669315).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References