5FHX

CRYSTAL STRUCTURE OF CODV IN COMPLEX WITH IL4 AT 2.55 Ang. RESOLUTION.

5FHX の概要

• エントリーDOI: 10.2210/pdb5fhx/pdb
• 分子名称: Interleukin-4, antibody fragment heavy-chain, Antibody fragment light chain, ... (5 entities in total)
• 機能のキーワード: cross-over dual variable immunoglobulin multifunctional biotherapeutic drug, codv, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 88028.23

構造登録者

Vallee, F.,Dupuy, A.,Rak, A. (登録日: 2015-12-22, 公開日: 2016-03-30, 最終更新日: 2024-11-06)

主引用文献

Steinmetz, A.,Vallee, F.,Beil, C.,Lange, C.,Baurin, N.,Beninga, J.,Capdevila, C.,Corvey, C.,Dupuy, A.,Ferrari, P.,Rak, A.,Wonerow, P.,Kruip, J.,Mikol, V.,Rao, E.
CODV-Ig, a universal bispecific tetravalent and multifunctional immunoglobulin format for medical applications.
Mabs, 8:867-878, 2016

PubMed Abstract: Bispecific immunoglobulins (Igs) typically contain at least two distinct variable domains (Fv) that bind to two different target proteins. They are conceived to facilitate clinical development of biotherapeutic agents for diseases where improved clinical outcome is obtained or expected by combination therapy compared to treatment by single agents. Almost all existing formats are linear in their concept and differ widely in drug-like and manufacture-related properties. To overcome their major limitations, we designed cross-over dual variable Ig-like proteins (CODV-Ig). Their design is akin to the design of circularly closed repeat architectures. Indeed, initial results showed that the traditional approach of utilizing (G4S)x linkers for biotherapeutics design does not identify functional CODV-Igs. Therefore, we applied an unprecedented molecular modeling strategy for linker design that consistently results in CODV-Igs with excellent biochemical and biophysical properties. CODV architecture results in a circular self-contained structure functioning as a self-supporting truss that maintains the parental antibody affinities for both antigens without positional effects. The format is universally suitable for therapeutic applications targeting both circulating and membrane-localized proteins. Due to the full functionality of the Fc domains, serum half-life extension as well as antibody- or complement-dependent cytotoxicity may support biological efficiency of CODV-Igs. We show that judicious choice in combination of epitopes and paratope orientations of bispecific biotherapeutics is anticipated to be critical for clinical outcome. Uniting the major advantages of alternative bispecific biotherapeutics, CODV-Igs are applicable in a wide range of disease areas for fast-track multi-parametric drug optimization.

PubMed: 26984268
DOI: 10.1080/19420862.2016.1162932

実験手法

X-RAY DIFFRACTION (2.55 Å)