Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization.
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.
Igawa
Tomoyuki
T
Chugai Pharmaceutical Co. Ltd., Fuji-Gotemba Research Laboratories, Shizuoka, Japan. igawatmy@chugai-pharm.co.jp
Ishii
Shinya
S
Tachibana
Tatsuhiko
T
Maeda
Atsuhiko
A
Higuchi
Yoshinobu
Y
Shimaoka
Shin
S
Moriyama
Chifumi
C
Watanabe
Tomoyuki
T
Takubo
Ryoko
R
Doi
Yoshiaki
Y
Wakabayashi
Tetsuya
T
Hayasaka
Akira
A
Kadono
Shoujiro
S
Miyazaki
Takuya
T
Haraya
Kenta
K
Sekimori
Yasuo
Y
Kojima
Tetsuo
T
Nabuchi
Yoshiaki
Y
Aso
Yoshinori
Y
Kawabe
Yoshiki
Y
Hattori
Kunihiro
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized; D000941:Antigens / Q000276:immunology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008252:Macaca fascicularis / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009500:Neutralization Tests / Q000379:methods*; D015202:Protein Engineering / Q000379:methods*; D019947:Receptors, Interleukin-6 / Q000276:immunology*; D020349:Surface Plasmon Resonance
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000941:Antigens; D019947:Receptors, Interleukin-6; C502936:tocilizumab