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.
Chugai Pharmaceutical Co. Ltd., Fuji-Gotemba Research Laboratories, Shizuoka, Japan. igawatmy@chugai-pharm.co.jp
Tomoyuki
T
Igawa
Shinya
S
Ishii
Tatsuhiko
T
Tachibana
Atsuhiko
A
Maeda
Yoshinobu
Y
Higuchi
Shin
S
Shimaoka
Chifumi
C
Moriyama
Tomoyuki
T
Watanabe
Ryoko
R
Takubo
Yoshiaki
Y
Doi
Tetsuya
T
Wakabayashi
Akira
A
Hayasaka
Shoujiro
S
Kadono
Takuya
T
Miyazaki
Kenta
K
Haraya
Yasuo
Y
Sekimori
Tetsuo
T
Kojima
Yoshiaki
Y
Nabuchi
Yoshinori
Y
Aso
Yoshiki
Y
Kawabe
Kunihiro
K
Hattori
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