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

Igawa, T., Ishii, S., Tachibana, T., Maeda, A., Higuchi, Y., Shimaoka, S., Moriyama, C., Watanabe, T., Takubo, R., Doi, Y., Wakabayashi, T., Hayasaka, A., Kadono, S., Miyazaki, T., Haraya, K., Sekimori, Y., Kojima, T., Nabuchi, Y., Aso, Y., Kawabe, Y., Hattori, K.
Journal   Nat Biotechnol.
Species  
Analytes Measured   IL-6R
Matrix Tested   Plasma
Year   2010
Volume   28
Page Numbers   1203-1207
Application   Cytokines and Chemokines
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.

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