Kisalu Neville K, Silva Pereira Lais D, Herman Jonathan D, Asokan Mangaiarkarasi, Ernste Keenan, Merriam Jonah, Liu Cuiping, DeMouth Megan E, Pegu Amarendra, Lofgren Mariah, Dillon Marlon, Bonilla Brian, MacVicar Ryan, Zur Yonatan, Kiyuka Patience, Flores-Garcia Yevel, Chakraborty Saborni, Nikolaeva Daria, Ogwang Rodney, Flynn Barbara, Francica Joseph, Pierson Theodore C, Koup Richard A, Zavala Fidel, Wang Taia T, Alter Galit, Idris Azza H, Seder Robert A
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD 20892, USA.
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.
Sci Transl Med. 2025 Apr 23;17(795):eadk6745. doi: 10.1126/scitranslmed.adk6745.
Antibodies mediate protection against a wide range of pathogens through binding and neutralizing the pathogen or through Fc-mediated effector functions. Human monoclonal antibodies (mAbs) CIS43LS and L9LS show high-affinity binding targeting distinct regions on the circumsporozoite protein (PfCSP) and are highly effective in preventing malaria in humans. However, the role of FcγR binding in protection by these mAbs has not been determined. Here, we assessed several Fc variants of CIS43LS and L9LS for protection against infection with transgenic parasite expressing PfCSP in mice. Limiting binding to FcγRs did not reduce protection compared to the parental mAbs in mice. To determine whether protection could be improved in vivo by Fc modification, we engineered Fc variant mAbs with increased binding to distinct FcγRs. Passive transfer of CIS43LS-DE and CIS43LS-DEAL variants resulted in an approximately two- to threefold reduction in the liver-stage parasite burden in C57BL/6 or human FcγR mice compared with the parental CIS43LS after challenge. CIS43LS-DEAL also enhanced protection of mice after mosquito bite challenge. Systems serology analysis revealed that the CIS43LS-DE and CIS43LS-DEAL variants could enhance human neutrophil and monocyte phagocytosis, as well as NK cell activation, compared with CIS43LS. However, similar Fc modifications incorporated into L9LS did not increase protection compared to the parental mAb. Overall, although FcγR binding by CIS43LS and L9LS is dispensable in mouse models of malaria, enhancing the binding of CIS43LS to FcγR showed a modest increase in the potency of this mAb.
抗体通过结合并中和病原体或通过Fc介导的效应功能介导针对多种病原体的保护作用。人单克隆抗体（mAb）CIS43LS和L9LS显示出针对环子孢子蛋白（PfCSP）上不同区域的高亲和力结合，并且在预防人类疟疾方面非常有效。然而，这些单克隆抗体通过FcγR结合发挥保护作用的机制尚未确定。在此，我们评估了CIS43LS和L9LS的几种Fc变体在小鼠中针对表达PfCSP的转基因寄生虫感染的保护作用。与亲本单克隆抗体相比，限制与FcγR的结合并未降低小鼠的保护作用。为了确定Fc修饰是否可以在体内增强保护作用，我们构建了与不同FcγR结合增加的Fc变体单克隆抗体。与亲本CIS43LS相比，CIS43LS-DE和CIS43LS-DEAL变体的被动转移导致C57BL/6或人FcγR小鼠肝期寄生虫负荷降低约两到三倍。CIS43LS-DEAL在蚊虫叮咬攻击后也增强了对小鼠的保护作用。系统血清学分析表明，与CIS43LS相比，CIS43LS-DE和CIS43LS-DEAL变体可以增强人中性粒细胞和单核细胞的吞噬作用以及NK细胞的活化。然而，与亲本单克隆抗体相比，将类似的Fc修饰引入L9LS并没有增加保护作用。总体而言，虽然CIS43LS和L9LS与FcγR的结合在疟疾小鼠模型中并非必需，但增强CIS43LS与FcγR的结合显示该单克隆抗体的效力有适度增加。
