New strategies are needed to reduce the incidence of malaria, and promising approaches include the development of vaccines and monoclonal antibodies (mAbs) that target the circumsporozoite protein (CSP). To select the best candidates and speed development, it is essential to standardize preclinical assays to measure the potency of such interventions in animal models. Two assay configurations were studied using transgenic Plasmodium berghei expressing Plasmodium falciparum full-length circumsporozoite protein. The assays measured (1) reduction in parasite infection of the liver (liver burden) following an intravenous (i.v) administration of sporozoites and (2) protection from parasitaemia following mosquito bite challenge. Two human CSP mAbs, AB311 and AB317, were compared for their ability to inhibit infection. Multiple independent experiments were conducted to define assay variability and resultant impact on the ability to discriminate differences in mAb functional activity. Overall, the assays produced highly consistent results in that all individual experiments showed greater functional activity for AB317 compared to AB311 as calculated by the dose required for 50% inhibition (ID50) as well as the serum concentration required for 50% inhibition (IC50). The data were then used to model experimental designs with adequate statistical power to rigorously screen, compare, and rank order novel anti-CSP mAbs. The results indicate that in vivo assays described here can provide reliable information for comparing the functional activity of mAbs. The results also provide guidance regarding selection of the appropriate experimental design, dose selection, and group sizes.

中文翻译：

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表征两个体内挑战模型以测量针对恶性疟原虫环子孢子蛋白的单克隆抗体的功能活性

需要新的策略来减少疟疾的发病率，并且有前途的方法包括开发针对环子孢子蛋白（CSP）的疫苗和单克隆抗体（mAb）。为了选择最佳候选者并加快开发速度，必须标准化临床前测定以测量此类干预措施在动物模型中的效力。使用表达恶性疟原虫全长环子孢子蛋白的转基因伯氏疟原虫研究了两种测定配置。该测定法测量了（1）静脉内（iv）子孢子给药后肝脏寄生虫感染（肝脏负担）的减少和（2）蚊虫叮咬攻击后免受寄生虫血症的侵袭。比较了两种人类CSP mAb AB311和AB317抑制感染的能力。进行了多次独立实验以定义测定变异性以及由此产生的对区分mAb功能活性差异的能力的影响。总体而言，该测定产生了高度一致的结果，因为通过50％抑制所需的剂量（I​​D50）和50％抑制所需的血清浓度（IC50）计算，与AB311相比，所有单独的实验均显示AB317具有更高的功能活性。然后将数据用于具有足够统计能力的实验设计模型，以严格筛选，比较和排序新型抗CSP单抗。结果表明，本文所述的体内分析可提供可靠的信息，用于比较mAb的功能活性。结果还为选择合适的实验设计，剂量选择，