Stefanutti Erin, Ramani Rashmi, Whitener Bradley, Dang Ha, Bélanger Simon, Somasundaram Logeshwaran, Cortina Karen, De Marco Anna, Tam Tommy, Chai Qingqing, Cameroni Elisabetta, Gupta Rajesh, Schmid Michael A, Miller Jessica L, Zumsteg Anna Brotcke, Purcell Lisa A, Drewry Lisa L
Vir Biotechnology, San Francisco, California, USA.
Vir Biotechnology, Bellinzona, Switzerland.
Microbiol Spectr. 2025 Jul 23:e0086325. doi: 10.1128/spectrum.00863-25.
Antibodies targeting the malaria circumsporozoite protein (CSP) can prophylactically protect against malaria by targeting parasites before they establish symptomatic blood-stage disease. Engineering the antibody Fc region to more effectively engage immune effector functions has produced therapeutic antibodies with enhanced potency against viral and oncological targets. However, whether Fc-dependent immune effector functions can contribute to the protection of malaria CSP mAbs or be further enhanced via engineering has been limitedly tested. Here, we report that Fc-dependent effector functions are required for achieving maximal protection via prophylactic treatment with the CSP mAb 317. We further report that Fc engineering modulated the activity of multiple CSP mAbs in multiple assays of effector function. Our studies revealed that the mAbs L9 and CIS43 were more potent drivers of antibody-dependent phagocytosis, NK activation and killing, and complement deposition. In contrast, 317, but not L9 and CIS43, drove enhanced activation of CSP-responsive T-cells after DC acquisition of mAb-complexed antigens. Collectively, our data suggest that effector function represents an important mechanism of anti-CSP antibodies with the potential to enhance activity through Fc engineering.IMPORTANCEMalaria disease imposes a major burden on global health, causing over half a million annual deaths. Recent clinical trials in humans have shown that therapeutic antibodies can provide prophylactic protection against malaria in target populations. However, the cost of goods for therapeutic antibodies is high, and the malaria disease burden is concentrated in resource-challenged regions. Engineering the antibody Fc domain to more efficiently engage the immune system is an appealing strategy to increase the potency of therapeutic antibodies but has been minimally tested for malaria. Here, we present evidence that the Fc domain of malaria therapeutic antibodies can confer protection in animal models and can be engineered for more potent stimulation of diverse parasite-targeting immune responses.
靶向疟疾环子孢子蛋白（CSP）的抗体可通过在寄生虫引发有症状的血液阶段疾病之前将其靶向，从而对疟疾起到预防性保护作用。对抗体Fc区域进行工程改造以更有效地发挥免疫效应功能，已产生了对病毒和肿瘤靶点具有更强效力的治疗性抗体。然而，Fc依赖性免疫效应功能是否有助于保护疟疾CSP单克隆抗体，或能否通过工程改造进一步增强，目前的测试还很有限。在此，我们报告称，通过CSP单克隆抗体317进行预防性治疗以实现最大程度的保护需要Fc依赖性效应功能。我们还报告称，Fc工程改造在多种效应功能测定中调节了多种CSP单克隆抗体的活性。我们的研究表明，单克隆抗体L9和CIS43在抗体依赖性吞噬作用、自然杀伤细胞激活与杀伤以及补体沉积方面是更强的驱动因素。相比之下，317（而非L9和CIS43）在树突状细胞获取单克隆抗体复合抗原后，促使CSP反应性T细胞的激活增强。总体而言，我们的数据表明效应功能是抗CSP抗体的一种重要机制，具有通过Fc工程改造增强活性的潜力。
重要性
疟疾给全球健康带来了沉重负担，每年导致超过50万人死亡。近期在人体进行的临床试验表明，治疗性抗体可为目标人群提供疟疾预防性保护。然而，治疗性抗体的生产成本高昂，而疟疾疾病负担集中在资源匮乏地区。对抗体Fc结构域进行工程改造以更有效地激活免疫系统，是提高治疗性抗体效力的一种有吸引力的策略，但在疟疾方面的测试极少。在此，我们提供证据表明，疟疾治疗性抗体的Fc结构域可在动物模型中提供保护，并且可以进行工程改造以更有效地刺激针对多种寄生虫的免疫反应。
