Peissert Frederik, Pedotti Mattia, Corbellari Riccardo, Simonelli Luca, De Gasparo Raoul, Tamagnini Elia, Plüss Louis, Elsayed Abdullah, Matasci Mattia, De Luca Roberto, Cassaniti Irene, Sammartino Jose' Camilla, Piralla Antonio, Baldanti Fausto, Neri Dario, Varani Luca
Philochem AG Libernstrasse 3 Otelfingen 8112 Switzerland.
Institute for Research in Biomedicine Università della Svizzera italiana (USI) Bellinzona 6500 Switzerland.
Glob Chall. 2023 Aug 21;7(10):2300088. doi: 10.1002/gch2.202300088. eCollection 2023 Oct.
Neutralizing monoclonal antibodies have achieved great efficacy and safety for the treatment of numerous infectious diseases. However, their neutralization potency is often rapidly lost when the target antigen mutates. Instead of isolating new antibodies each time a pathogen variant arises, it can be attractive to adapt existing antibodies, making them active against the new variant. Potential benefits of this approach include reduced development time, cost, and regulatory burden. Here a methodology is described to rapidly evolve neutralizing antibodies of proven activity, improving their function against new pathogen variants without losing efficacy against previous ones. The reported procedure is based on structure-guided affinity maturation using combinatorial mutagenesis and phage display technology. Its use against the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is demonstrated, but it is suitable for any other pathogen. As proof of concept, the method is applied to CoV-X2, a human bispecific antibody that binds with high affinity to the early SARS-CoV-2 variants but lost neutralization potency against Delta. Antibodies emerging from the affinity maturation selection exhibit significantly improved neutralization potency against Delta and no loss of efficacy against the other viral sequences tested. These results illustrate the potential application of structure-guided affinity maturation in facilitating the rapid adaptation of neutralizing antibodies to pathogen variants.
中和性单克隆抗体在治疗多种传染病方面已取得了显著的疗效和安全性。然而，当靶抗原发生突变时，它们的中和效力常常会迅速丧失。与其每次病原体变体出现时都分离新的抗体，对现有抗体进行改造使其对新变体具有活性可能更具吸引力。这种方法的潜在好处包括缩短开发时间、降低成本以及减轻监管负担。本文描述了一种方法，可快速进化已证实具有活性的中和抗体，提高其针对新病原体变体的功能，同时又不丧失对先前变体的效力。所报道的程序基于使用组合诱变和噬菌体展示技术的结构导向亲和力成熟。文中展示了其针对新型严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的应用，但它适用于任何其他病原体。作为概念验证，该方法应用于CoV-X2，一种与人双特异性抗体，它与早期SARS-CoV-2变体具有高亲和力，但对Delta变体失去了中和效力。从亲和力成熟筛选中产生的抗体对Delta变体显示出显著提高的中和效力，并且对测试的其他病毒序列没有效力损失。这些结果说明了结构导向亲和力成熟在促进中和抗体快速适应病原体变体方面的潜在应用。
