Reveiz Mateo, Tripathi Prabhanshu, Da Silva Pereira Lais, Kiyuka Patience Kerubo, Liu Tracy, Yang Yongping, Zhang Baoshan, Benmohamed Dorra, Bonilla Brian G, Carruthers Carl W, Dillon Marlon, Gowetski Daniel, Kratochvil Sven, Lagos Gabriella, Lofgren Mariah, Loukinov Ivan, Mathis-Torres Shamika, Schaub Andrew J, Scheideman Elizabeth, Schön Arne, Shen Chen-Hsiang, Flores-Garcia Yevel, Zavala Fidel, Batista Facundo D, Idris Azza H, Seder Robert A, Kwong Peter D, Rawi Reda
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Kenya Medical Research Institute, Centre for Geographic Medicine Research Coast, P.O. Box 230-80108, Kilifi, Kenya.
iScience. 2025 Jun 14;28(7):112903. doi: 10.1016/j.isci.2025.112903. eCollection 2025 Jul 18.
The monoclonal antibody CIS43 preferentially binds the junctional region of circumsporozoite protein (PfCSP) and is highly protective in humans. Here, we develop an pipeline to improve antigen-antibody interaction energies and apply it to CIS43 variants elicited in CIS43-germline knock-in mice. Improved binding of CIS43 variants to the CIS43 junctional epitope (PfCSP peptide 21) was achieved by introducing single and double amino acid substitutions in the peptide 21-proximal heavy- and light-chain-variable regions. The best designed variant, antibody P3-43-LS, was 2- to 3-fold more protective than antibody CIS43-LS, the clinical version of CIS43 with half-life extending leucine-serine (LS) mutations, and had comparable protection to the current best-in-class antibody (iGL-CIS43.D3-LS) to this region. Crystal structures of the improved antibodies revealed atomic-level interactions accounting for gains in binding affinity. This approach to improve antibody affinity can thus be used to enhance potency of PfCSP monoclonal antibodies.
单克隆抗体CIS43优先结合环子孢子蛋白（PfCSP）的连接区，对人类具有高度保护作用。在此，我们开发了一种提高抗原-抗体相互作用能的流程，并将其应用于在CIS43种系敲入小鼠中产生的CIS43变体。通过在肽21近端的重链和轻链可变区引入单氨基酸和双氨基酸取代，实现了CIS43变体与CIS43连接表位（PfCSP肽21）结合的改善。设计最佳的变体抗体P3-43-LS的保护作用比抗体CIS43-LS（具有延长半衰期的亮氨酸-丝氨酸（LS）突变的CIS43临床版本）强2至3倍，并且与该区域目前最佳的同类抗体（iGL-CIS43.D3-LS）具有相当的保护作用。改进后抗体的晶体结构揭示了导致结合亲和力增加的原子水平相互作用。因此，这种提高抗体亲和力的方法可用于增强PfCSP单克隆抗体的效力。
