Development of Monoclonal Antibody (Mab) Biologics against Neonatal Candidiasis

抗新生儿念珠菌病单克隆抗体 (Mab) 生物制剂的开发

基本信息

批准号：
8719015
负责人：
Jose L. Lopez-Ribot
金额：
$ 7.35万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8719015
关键词：
Adult Amphotericin B Animal Model Antibiotics Antibodies Antibody Formation Antibody Therapy Antifungal Agents Antifungal Therapy Antigens Autoimmune Diseases Azoles Biological Biological Products Birth Weight Candida albicans Candidiasis Chemosensitization Clinic Comorbidity Data Development Disease Disseminated candidiasis Drug or Chemical Gestational Age Gram-Negative Bacteria Grant Health Care Costs Hospital Economics Host Defense Human Hybridomas Immune system Immunodominant Antigens In Vitro Infection Innovative Therapy Lead Length of Stay Life Medical Methodology Modeling Monoclonal Antibodies Morbidity - disease rate Mus Mycoses Neonatal Neurodevelopmental Impairment Organ Survival Paper Patients Pharmaceutical Preparations Premature Infant Preparation Resistance Resistance development Risk Role Seminal Serum Specificity Surface Technology The science of Mycology Variant Very Low Birth Weight Infant base cancer therapy chemotherapy combat economic cost in vivo infectious disease treatment interest large scale production mortality neonate novel prevent protective effect public health relevance pup research study small molecule

项目摘要

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.

描述（由申请人提供）：念珠菌病代表了住院的患者和白色念珠菌中最常见的真菌感染，仍然是念珠菌病的主要病因学药物，因为这种原本正常的人类的正常人类能够在不断扩大的免疫表征患者中引起危及生命的感染。新生儿，尤其是非常低的出生体重（VLBW）婴儿，非常容易受到念珠菌病的影响，这主要是由于其不成熟的免疫系统。这种风险随着出生体重和胎龄的减轻而增加。实际上，念珠菌病现在代表了VLBW新生儿中第二大常见的感染。值得注意的是，这些感染的死亡率高（尽管抗真菌治疗，大约是45％），是由于革兰氏阳性和革兰氏阴性细菌而引起的感染的两倍。新生儿念珠菌病还增加了逐渐的合并症（即神经发育障碍），住院时间和经济成本。显然，这些高死亡率表明当前的抗真菌治疗仍然无效，UE主要涉及有限的抗真菌药物的武器库以及对大多数抗真菌类别类别的耐药性的出现。在包括I新生儿在内的念珠菌病治疗中遇到的这些困难导致人们对寻找创新疗法的兴趣增加了。抗体疗法构成了使用“小分子”或“化学”药物的经典疗法的非常有吸引力的替代品。在医学真菌学领域，Casadevall组的开创性论文导致对抗体的作用进行了重新评估，并且对基于抗体的疗法的开发对治疗真菌感染的疗法产生了兴趣。尽管事实是，抗体反应在宿主防御念珠菌病中的作用仍然引起争议，但最近已最终证明，单克隆抗体（MABS）在相关动物模型中被动施用单克隆抗体（MAB）在传播念珠菌病期间有助于保护。我们的主要假设是，MAB的发展将增加针对念珠菌病的治疗选择，并特别强调新生儿念珠菌病。由于它们的生物学活动，包括在动物感染模型中表明其保护作用的初步数据，我们已经确定了三个非常有前途的mAb（3H3，1H4和C7），它们是该提案的基础。因此，这项小赠款中的实验将进一步推进这些单克重，作为开发新生物制剂来开发新生儿念珠菌病的抗体疗法的候选者。为此，我将确定它们在被动转移保护方面的功效（血清治疗）实验使用新生儿中浸润性念珠菌病的新型鼠模型，ii）确定这些MAB与临床使用的抗真菌药物之间组合的体外和体内疗效。