Engineering a HER2-specific antibody-drug conjugate to increase lysosomal delivery and therapeutic efficacy

We improve the potency of antibody-drug conjugates (ADCs) containing the HER2-specific antibody pertuzumab by reducing their affinity for HER2 by >250-fold at acidic endosomal pH relative to near neutral pH. These engineered pertuzumab variants show increased lysosomal delivery and cytotoxicity t...

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Detalles Bibliográficos
Autores principales: Kang, Jeffrey C., Sun, Wei, Khare, Priyanka, Karimi, Mostafa, Wang, Xiaoli, Shen, Yang, Ober, Raimund J., Ward, E. Sally
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668989/
https://www.ncbi.nlm.nih.gov/pubmed/30936563
http://dx.doi.org/10.1038/s41587-019-0073-7
Descripción
Sumario:We improve the potency of antibody-drug conjugates (ADCs) containing the HER2-specific antibody pertuzumab by reducing their affinity for HER2 by >250-fold at acidic endosomal pH relative to near neutral pH. These engineered pertuzumab variants show increased lysosomal delivery and cytotoxicity towards tumor cells expressing intermediate HER2 levels. In HER2(int) xenograft tumor models in mice, the variants show higher therapeutic efficacy than the parent ADC and a clinically-approved HER2-specific ADC.

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