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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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
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author Kang, Jeffrey C.
Sun, Wei
Khare, Priyanka
Karimi, Mostafa
Wang, Xiaoli
Shen, Yang
Ober, Raimund J.
Ward, E. Sally
author_facet Kang, Jeffrey C.
Sun, Wei
Khare, Priyanka
Karimi, Mostafa
Wang, Xiaoli
Shen, Yang
Ober, Raimund J.
Ward, E. Sally
author_sort Kang, Jeffrey C.
collection PubMed
description 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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spelling pubmed-66689892019-10-01 Engineering a HER2-specific antibody-drug conjugate to increase lysosomal delivery and therapeutic efficacy Kang, Jeffrey C. Sun, Wei Khare, Priyanka Karimi, Mostafa Wang, Xiaoli Shen, Yang Ober, Raimund J. Ward, E. Sally Nat Biotechnol Article 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. 2019-04-01 2019-05 /pmc/articles/PMC6668989/ /pubmed/30936563 http://dx.doi.org/10.1038/s41587-019-0073-7 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Kang, Jeffrey C.
Sun, Wei
Khare, Priyanka
Karimi, Mostafa
Wang, Xiaoli
Shen, Yang
Ober, Raimund J.
Ward, E. Sally
Engineering a HER2-specific antibody-drug conjugate to increase lysosomal delivery and therapeutic efficacy
title Engineering a HER2-specific antibody-drug conjugate to increase lysosomal delivery and therapeutic efficacy
title_full Engineering a HER2-specific antibody-drug conjugate to increase lysosomal delivery and therapeutic efficacy
title_fullStr Engineering a HER2-specific antibody-drug conjugate to increase lysosomal delivery and therapeutic efficacy
title_full_unstemmed Engineering a HER2-specific antibody-drug conjugate to increase lysosomal delivery and therapeutic efficacy
title_short Engineering a HER2-specific antibody-drug conjugate to increase lysosomal delivery and therapeutic efficacy
title_sort engineering a her2-specific antibody-drug conjugate to increase lysosomal delivery and therapeutic efficacy
topic Article
url 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
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