5UDC

Crystal Structure of RSV F A2 Bound to MEDI8897

5UDC の概要

• エントリーDOI: 10.2210/pdb5udc/pdb
• 関連するPDBエントリー: 5UDD 5UDE
• 分子名称: MEDI8897 Fab Heavy Chain, MEDI8897 Fab Light Chain, Fusion glycoprotein F0, ... (5 entities in total)
• 機能のキーワード: immune system, antibody, fusion glycoprotein, virus, viral protein-immune system complex, viral protein/immune system
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 334058.38

構造登録者

McLellan, J.S. (登録日: 2016-12-26, 公開日: 2017-05-17, 最終更新日: 2024-11-20)

主引用文献

Zhu, Q.,McLellan, J.S.,Kallewaard, N.L.,Ulbrandt, N.D.,Palaszynski, S.,Zhang, J.,Moldt, B.,Khan, A.,Svabek, C.,McAuliffe, J.M.,Wrapp, D.,Patel, N.K.,Cook, K.E.,Richter, B.W.M.,Ryan, P.C.,Yuan, A.Q.,Suzich, J.A.
A highly potent extended half-life antibody as a potential RSV vaccine surrogate for all infants.
Sci Transl Med, 9:-, 2017

PubMed Abstract: Prevention of respiratory syncytial virus (RSV) illness in all infants is a major public health priority. However, no vaccine is currently available to protect this vulnerable population. Palivizumab, the only approved agent for RSV prophylaxis, is limited to high-risk infants, and the cost associated with the requirement for dosing throughout the RSV season makes its use impractical for all infants. We describe the development of a monoclonal antibody as potential RSV prophylaxis for all infants with a single intramuscular dose. MEDI8897*, a highly potent human antibody, was optimized from antibody D25, which targets the prefusion conformation of the RSV fusion (F) protein. Crystallographic analysis of Fab in complex with RSV F from subtypes A and B reveals that MEDI8897* binds a highly conserved epitope. MEDI8897* neutralizes a diverse panel of RSV A and B strains with >50-fold higher activity than palivizumab. At similar serum concentrations, prophylactic administration of MEDI8897* was ninefold more potent than palivizumab at reducing pulmonary viral loads by >3 logs in cotton rats infected with either RSV A or B subtypes. MEDI8897 was generated by the introduction of triple amino acid substitutions (YTE) into the Fc domain of MEDI8897*, which led to more than threefold increased half-life in cynomolgus monkeys compared to non-YTE antibody. Considering the pharmacokinetics of palivizumab in infants, which necessitates five monthly doses for protection during an RSV season, the high potency and extended half-life of MEDI8897 support its development as a cost-effective option to protect all infants from RSV disease with once-per-RSV-season dosing in the clinic.

PubMed: 28469033
DOI: 10.1126/scitranslmed.aaj1928

実験手法

X-RAY DIFFRACTION (3.45 Å)