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Nat Biotechnol. 2010 Nov;28(11):1203-7. doi: 10.1038/nbt.1691. Epub 2010 Oct 17.

Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization.

Author information

1
Chugai Pharmaceutical Co. Ltd., Fuji-Gotemba Research Laboratories, Shizuoka, Japan. igawatmy@chugai-pharm.co.jp

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.

PMID:
20953198
DOI:
10.1038/nbt.1691
[Indexed for MEDLINE]

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