Abstract
We improve the potency of antibody-drug conjugates (ADCs) containing the human epidermal growth factor receptor 2 (HER2)-specific antibody pertuzumab by substantially reducing their affinity for HER2 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 HER2int xenograft tumor models in mice, the variants show higher therapeutic efficacy than the parent ADC and a clinically approved HER2-specific ADC.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal, Humanized / immunology
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Antibodies, Monoclonal, Humanized / therapeutic use*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / therapeutic use
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / immunology
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / immunology
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Cytotoxicity, Immunologic / drug effects
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Drug Delivery Systems*
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Female
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Humans
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Immunoconjugates / immunology
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Immunoconjugates / therapeutic use*
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Lysosomes / immunology
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Mice
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Receptor, ErbB-2 / immunology*
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Immunoconjugates
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ERBB2 protein, human
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Receptor, ErbB-2
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pertuzumab