Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2010-11

AUTHORS

Tomoyuki Igawa, Shinya Ishii, Tatsuhiko Tachibana, Atsuhiko Maeda, Yoshinobu Higuchi, Shin Shimaoka, Chifumi Moriyama, Tomoyuki Watanabe, Ryoko Takubo, Yoshiaki Doi, Tetsuya Wakabayashi, Akira Hayasaka, Shoujiro Kadono, Takuya Miyazaki, Kenta Haraya, Yasuo Sekimori, Tetsuo Kojima, Yoshiaki Nabuchi, Yoshinori Aso, Yoshiki Kawabe, Kunihiro Hattori

ABSTRACT

For many antibodies, each antigen-binding site binds to only one antigen molecule during the antibody's lifetime in plasma. To increase the number of cycles of antigen binding and lysosomal degradation, we engineered tocilizumab (Actemra), an antibody against the IL-6 receptor (IL-6R), to rapidly dissociate from IL-6R within the acidic environment of the endosome (pH 6.0) while maintaining its binding affinity to IL-6R in plasma (pH 7.4). Studies using normal mice and mice expressing human IL-6R suggested that this pH-dependent IL-6R dissociation within the acidic environment of the endosome resulted in lysosomal degradation of the previously bound IL-6R while releasing the free antibody back to the plasma to bind another IL-6R molecule. In cynomolgus monkeys, an antibody with pH-dependent antigen binding, but not an affinity-matured variant, significantly improved the pharmacokinetics and duration of C-reactive protein inhibition. Engineering pH dependency into the interactions of therapeutic antibodies with their targets may enable them to be delivered less frequently or at lower doses. More... »

PAGES

1203

Journal

TITLE

Nature Biotechnology

ISSUE

11

VOLUME

28

Author Affiliations

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nbt.1691

    DOI

    http://dx.doi.org/10.1038/nbt.1691

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1050662544

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/20953198


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