COVID治療薬の有効性を回復させる(Restoring the efficacy of COVID therapeutics)

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2024-06-13 ロスアラモス国立研究所(LANL)

ロスアラモス国立研究所の研究者たちは、COVID治療薬エヴシェルドの効果を回復させるための取り組みを行っています。この研究成果はNature誌に発表されました。エヴシェルドは免疫抑制患者向けの抗体治療薬で、オミクロン変異株の出現により効果が減少しました。研究チームは、GUIDEという高性能計算、シミュレーション、機械学習を組み合わせた手法を用いて、抗体の結合親和性を最適化し、効果を回復させました。ロスアラモスの科学者たちは酵母細胞を使った高スループットスクリーニングで450の抗体配列を評価し、迅速に有効な抗体を特定しました。GUIDEプログラムは、次のパンデミックに備えて、薬剤開発を加速するために設立されました。

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オミクロンに対する臨床抗体の効力を計算で復元する Computationally restoring the potency of a clinical antibody against Omicron

Thomas A. Desautels,Kathryn T. Arrildt,Adam T. Zemla,Edmond Y. Lau,Fangqiang Zhu,Dante Ricci,Stephanie Cronin,Seth J. Zost,Elad Binshtein,Suzanne M. Scheaffer,Bernadeta Dadonaite,Brenden K. Petersen,Taylor B. Engdahl,Elaine Chen,Laura S. Handal,Lynn Hall,John W. Goforth,Denis Vashchenko,Sam Nguyen,Dina R. Weilhammer,Jacky Kai-Yin Lo,Bonnee Rubinfeld,Edwin A. Saada,Tracy Weisenberger,Tri-lab COVID-19 Consortium,… Daniel M. Faissol
Nature  Published:08 May 2024
DOI:https://doi.org/10.1038/s41586-024-07385-1

COVID治療薬の有効性を回復させる(Restoring the efficacy of COVID therapeutics)

Abstract

The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs1,2,3 and revealed how quickly viral escape can curtail effective options4,5. When the SARS-CoV-2 Omicron variant emerged in 2021, many antibody drug products lost potency, including Evusheld and its constituent, cilgavimab4,5,6. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination4 and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign and renew the efficacy of COV2-2130 against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and subsequent variants of concern, and provides protection in vivo against the strains tested: WA1/2020, BA.1.1 and BA.5. Deep mutational scanning of tens of thousands of pseudovirus variants reveals that 2130-1-0114-112 improves broad potency without increasing escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Our computational approach does not require experimental iterations or pre-existing binding data, thus enabling rapid response strategies to address escape variants or lessen escape vulnerabilities.

有機化学・薬学
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