Development of Monoclonal Antibody (Mab) Biologics against Neonatal Candidiasis

描述（由申请方提供）：念珠菌病是住院患者中最常见的真菌感染，白色念珠菌仍然是念珠菌病的主要病原体，因为这种人类正常的念珠菌能够在越来越多的免疫功能低下患者中引起危及生命的感染。新生儿，特别是极低出生体重（VLBW）婴儿，非常容易感染念珠菌病，主要是由于他们的免疫系统不成熟;这种风险随着出生体重和胎龄的降低而增加。事实上，念珠菌病现在是VLBW新生儿的第二大常见感染。值得注意的是，这些感染具有不可接受的高死亡率（尽管进行了抗真菌治疗，仍约为45%），是革兰氏阳性菌和革兰氏阴性菌感染相关死亡率的两倍。新生儿念珠菌病还增加了并发症（即神经发育障碍）、住院时间和经济成本。显然，这些高死亡率表明，目前的抗真菌治疗仍然是无效的，主要是由于有限的抗真菌药物库和出现耐药性的大多数类别的抗真菌药物。在治疗念珠菌病（包括新生儿）中遇到的这些困难导致人们对寻找创新疗法的兴趣增加。抗体疗法构成了使用“小分子”或“化学”药物的经典治疗的非常有吸引力的替代方案。在医学真菌学领域，Casadevall小组的开创性论文导致了对抗体作用的重新评估，并重新引起了人们对开发基于抗体的治疗真菌感染的疗法的兴趣。尽管抗体应答在宿主防御念珠菌病中的作用仍存在争议，但最近已最终证明，被动给予单克隆抗体（Mab）有助于在相关动物模型中的播散性念珠菌病期间提供保护。我们的主要假设是，单克隆抗体的发展将增加对念珠菌病的治疗选择，特别是对新生儿念珠菌病。由于它们的生物活性，包括表明它们在感染动物模型中的保护作用的初步数据，我们已经鉴定了三种非常有前途的单克隆抗体（3 H3、1H 4和C7），它们作为本提议的基础。因此，这项小额资助的实验将进一步推进这些单克隆抗体作为开发新生儿念珠菌病抗体治疗新生物制剂的候选物;为此，我们将i）确定它们在保护（血清）被动转移中的功效。 治疗）实验，和ii）确定这些Mab和临床使用的抗真菌药物之间的组合的体外和体内功效。

DESCRIPTION (provided by applicant): Candidiasis represents the most common fungal infection in hospitalized patients and Candida albicans remains the main etiologic agent of candidiasis, as this otherwise normal commensal of humans is capable of causing life-threatening infections in an expanding spectrum of immunocompromissed patients. Neonates, and in particular very low birth weight (VLBW) infants, are highly susceptible to candidiasis, mostly due to their immature immune system; and this risk increases with decreasing birth weight and gestational age. In fact, candidiasis represents now the second most common infection in VLBW neonates. Of note, these infections carry unacceptably high mortality rates (about 45% despite antifungal treatment), double than those associated with infections due to gram positive and gram negative bacteria. Neonatal candidiasis also adds incremental co-morbidity (i.e. neurodevelopmental impairment), length of hospital stay and economic costs. Clearly, these high mortality rates indicate that current antifungal therapy is still ineffective, ue mainly to the limited arsenal of antifungal drugs and the emergence of resistance to most classes of antifungals. These difficulties encountered in the treatment of candidiasis, including i neonates, have led to an increased interest in the search for innovative therapies. Antibody therapy constitutes a very attractive alternative to classical treatment using "small molecule" or "chemical" drugs. In the field of Medical Mycology, seminal papers by the Casadevall group led to a reappraisal of the role of antibodies and a revived interest in the development of antibody-based therapies for the treatment of fungal infections. Despite the fact that the role of antibody response in host defense against candidiasis remains controversial, recently it has been conclusively demonstrated that passive administration of monoclonal antibodies (Mabs) contributes to protection during disseminated candidiasis in relevant animal models. Our main hypothesis is that the development of Mabs will increase the treatment options against candidiasis, with special emphasis on neonatal candidiasis. By virtue of their biological activities, including preliminary data indicating their protective effect in an animal model of infection, we have identified three very promising Mabs (3H3, 1H4 and C7) which serve as the basis of this proposal. Thus, experiments in this small grant will further advance these Mabs as candidates for the development of new biologics for the antibody-therapy of neonatal candidiasis; for which we will i) determine their efficacy in passive transfer of protection (serum therapy) experiments using a novel murine model of invasive candidiasis in neonates, and ii) determine the in vitro and in vivo efficacy of combinations between these Mabs and clinically used antifungal drugs.