5JZ7

NGF IN COMPLEX WITH MEDI578 scFv

5JZ7 の概要

• エントリーDOI: 10.2210/pdb5jz7/pdb
• 分子名称: Beta-nerve growth factor, MEDI578 scFv, heavy chain, MEDI578 scFv, light chain (3 entities in total)
• 機能のキーワード: antibody, complex, epitope, ngf, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Secreted: P01138
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 156350.41

構造登録者

Olsson, L.-L.,Aagaard, A. (登録日: 2016-05-16, 公開日: 2017-01-11, 最終更新日: 2024-11-13)

主引用文献

Dobson, C.L.,Devine, P.W.,Phillips, J.J.,Higazi, D.R.,Lloyd, C.,Popovic, B.,Arnold, J.,Buchanan, A.,Lewis, A.,Goodman, J.,van der Walle, C.F.,Thornton, P.,Vinall, L.,Lowne, D.,Aagaard, A.,Olsson, L.L.,Ridderstad Wollberg, A.,Welsh, F.,Karamanos, T.K.,Pashley, C.L.,Iadanza, M.G.,Ranson, N.A.,Ashcroft, A.E.,Kippen, A.D.,Vaughan, T.J.,Radford, S.E.,Lowe, D.C.
Engineering the surface properties of a human monoclonal antibody prevents self-association and rapid clearance in vivo.
Sci Rep, 6:38644-38644, 2016

PubMed Abstract: Uncontrolled self-association is a major challenge in the exploitation of proteins as therapeutics. Here we describe the development of a structural proteomics approach to identify the amino acids responsible for aberrant self-association of monoclonal antibodies and the design of a variant with reduced aggregation and increased serum persistence in vivo. We show that the human monoclonal antibody, MEDI1912, selected against nerve growth factor binds with picomolar affinity, but undergoes reversible self-association and has a poor pharmacokinetic profile in both rat and cynomolgus monkeys. Using hydrogen/deuterium exchange and cross-linking-mass spectrometry we map the residues responsible for self-association of MEDI1912 and show that disruption of the self-interaction interface by three mutations enhances its biophysical properties and serum persistence, whilst maintaining high affinity and potency. Immunohistochemistry suggests that this is achieved via reduction of non-specific tissue binding. The strategy developed represents a powerful and generic approach to improve the properties of therapeutic proteins.

PubMed: 27995962
DOI: 10.1038/srep38644

実験手法

X-RAY DIFFRACTION (3.4 Å)