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Mol Cancer Ther ; 19(9): 1833-1843, 2020 09.
Article in English | MEDLINE | ID: mdl-32669315

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 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.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Breast Neoplasms/drug therapy , Drug Resistance, Neoplasm/drug effects , Oligopeptides/administration & dosage , Receptor, ErbB-2/metabolism , Stomach Neoplasms/drug therapy , Ado-Trastuzumab Emtansine/pharmacology , Ado-Trastuzumab Emtansine/therapeutic use , Animals , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal/pharmacology , Breast Neoplasms/blood , Breast Neoplasms/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Down-Regulation , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Oligopeptides/pharmacokinetics , Oligopeptides/pharmacology , Stomach Neoplasms/blood , Stomach Neoplasms/metabolism , Xenograft Model Antitumor Assays
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