5AZE

Fab fragment of calcium-dependent antigen binding antibody, 6RL#9

5AZE の概要

• エントリーDOI: 10.2210/pdb5aze/pdb
• 分子名称: 6RL#9 FAB LIGHT CHAIN, 6RL#9 FAB HEAVY CHAIN, CALCIUM ION, ... (4 entities in total)
• 機能のキーワード: calcium-dependent, recycling antibody, immune system
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 47261.58

構造登録者

Kadono, S.,Hironiwa, N.,Ishii, S.,Igawa, T.,Hattori, K. (登録日: 2015-10-02, 公開日: 2015-11-11, 最終更新日: 2024-10-30)

主引用文献

Hironiwa, N.,Ishii, S.,Kadono, S.,Iwayanagi, Y.,Mimoto, F.,Habu, K.,Igawa, T.,Hattori, K.
Calcium-dependent antigen binding as a novel modality for antibody recycling by endosomal antigen dissociation
Mabs, 8:65-73, 2016

PubMed Abstract: The pH-dependent antigen binding antibody, termed a recycling antibody, has recently been reported as an attractive type of second-generation engineered therapeutic antibody. A recycling antibody can dissociate antigen in the acidic endosome, and thus bind to its antigen multiple times. As a consequence, a recycling antibody can neutralize large amounts of antigen in plasma. Because this approach relies on histidine residues to achieve pH-dependent antigen binding, which could limit the epitopes that can be targeted and affect the rate of antigen dissociation in the endosome, we explored an alternative approach for generating recycling antibodies. Since calcium ion concentration is known to be lower in endosome than in plasma, we hypothesized that an antibody with antigen-binding properties that are calcium-dependent could be used as recycling antibody. Here, we report a novel anti-interleukin-6 receptor (IL-6R) antibody, identified from a phage library that binds to IL-6R only in the presence of a calcium ion. Thermal dynamics and a crystal structure study revealed that the calcium ion binds to the heavy chain CDR3 region (HCDR3), which changes and possibly stabilizes the structure of HCDR3 to make it bind to antigen calcium dependently (PDB 5AZE). In vitro and in vivo studies confirmed that this calcium-dependent antigen-binding antibody can dissociate its antigen in the endosome and accelerate antigen clearance from plasma, making it a novel approach for generating recycling antibody.

PubMed: 26496237
DOI: 10.1080/19420862.2015.1110660

実験手法

X-RAY DIFFRACTION (2.2 Å)