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.
Mol Cancer Ther
; 19(9): 1833-1843, 2020 09.
Article
em En
| 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oligopeptídeos
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Neoplasias Gástricas
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Neoplasias da Mama
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Receptor ErbB-2
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Resistencia a Medicamentos Antineoplásicos
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Anticorpos Monoclonais
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article