Engineered Multivalent Nanobodies Potently and Broadly Neutralize SARS-CoV-2 Variants,Advanced Therapeutics

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Engineered Multivalent Nanobodies Potently and Broadly Neutralize SARS-CoV-2 Variants
Advanced Therapeutics ( IF 3.7 ) Pub Date : 2021-08-02 , DOI: 10.1002/adtp.202100099
Jennifer M Zupancic _{1,

2} , John S Schardt _{1,

2,

3} , Alec A Desai _{1,

2} , Emily K Makowski _{2,

3} , Matthew D Smith _{1,

2} , Ghasidit Pornnoppadol _{2,

3} , Mayara Garcia de Mattos Barbosa ₄ , Marilia Cascalho _{4,

5} , Thomas M Lanigan ₆ , Peter M Tessier _{1,

2,

3,

7}

Affiliation

The COVID-19 pandemic continues to be a severe threat to human health, especially due to current and emerging SARS-CoV-2 variants with potential to escape humoral immunity developed after vaccination or infection. The development of broadly neutralizing antibodies that engage evolutionarily conserved epitopes on coronavirus spike proteins represents a promising strategy to improve therapy and prophylaxis against SARS-CoV-2 and variants thereof. Herein, a facile multivalent engineering approach is employed to achieve large synergistic improvements in the neutralizing activity of a SARS-CoV-2 cross-reactive nanobody (VHH-72) initially generated against SARS-CoV. This synergy is epitope specific and is not observed for a second high-affinity nanobody against a non-conserved epitope in the receptor-binding domain. Importantly, a hexavalent VHH-72 nanobody retains binding to spike proteins from multiple highly transmissible SARS-CoV-2 variants (B.1.1.7 and B.1.351) and potently neutralizes them. Multivalent VHH-72 nanobodies also display drug-like biophysical properties, including high stability, high solubility, and low levels of non-specific binding. The unique neutralizing and biophysical properties of VHH-72 multivalent nanobodies make them attractive as therapeutics against SARS-CoV-2 variants.

中文翻译：

工程化多价纳米抗体可有效且广泛地中和 SARS-CoV-2 变异体

COVID-19 大流行仍然对人类健康构成严重威胁，特别是由于当前和新出现的 SARS-CoV-2 变种有可能逃避疫苗接种或感染后产生的体液免疫。开发广泛中和抗体，结合冠状病毒刺突蛋白上进化上保守的表位，是改善 SARS-CoV-2 及其变体的治疗和预防的一种有前景的策略。在此，采用一种简便的多价工程方法来实现最初针对 SARS-CoV 产生的 SARS-CoV-2 交叉反应纳米抗体 (VHH-72) 的中和活性的大幅协同改善。这种协同作用是表位特异性的，并且对于针对受体结合域中的非保守表位的第二个高亲和力纳米抗体没有观察到。重要的是，六价 VHH-72 纳米抗体保留了与多种高度传播的 SARS-CoV-2 变体（B.1.1.7 和 B.1.351）的刺突蛋白的结合，并有效中和它们。多价 VHH-72 纳米抗体还表现出类似药物的生物物理特性，包括高稳定性、高溶解度和低水平的非特异性结合。 VHH-72 多价纳米抗体独特的中和和生物物理特性使其成为针对 SARS-CoV-2 变体的有吸引力的治疗方法。

更新日期：2021-08-25

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