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

• 批准号: 8425740
• 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
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8425740
• 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

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，因为这种正常的人类共生菌能够在不断扩大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，极易感染念珠菌病，这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 新生儿中第二常见的感染。值得注意的是，这些感染的死亡率高得令人无法接受（尽管进行了抗真菌治疗，死亡率仍约为 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。新生儿念珠菌病还会增加并发症（即神经发育障碍）、住院时间和经济成本。显然，这些高死亡率表明当前的抗真菌治疗仍然无效，这主要是由于抗真菌药物库有限以及对大多数类别的抗真菌药物出现了耐药性。在治疗念珠菌病（包括新生儿念珠菌病）时遇到的这些困难引起了人们对寻找创新疗法的兴趣增加。抗体疗法是使用“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 小组的开创性论文引发了人们对抗体作用的重新评估，并重新燃起了人们对开发基于抗体的真菌感染疗法的兴趣。尽管抗体反应在宿主对抗念珠菌病的防御中的作用仍然存在争议，但最近已经明确证明，被动施用单克隆抗体 (Mab) 有助于在相关动物模型中传播念珠菌病期间提供保护。我们的主要假设是单克隆抗体的开发将增加针对念珠菌病的治疗选择，特别是新生儿念珠菌病。凭借其生物活性，包括表明其在感染动物模型中的保护作用的初步数据，我们已经确定了三种非常有前途的单克隆抗体（3H3、1H4 和 C7），它们作为本提案的基础。因此，这笔小额资助的实验将进一步推动这些单克隆抗体成为开发用于新生儿念珠菌病抗体治疗的新生物制剂的候选者；为此，我们将 i) 确定它们在被动保护转移中的功效（血清 治疗）使用新生儿侵袭性念珠菌病的新型小鼠模型进行实验，ii）确定这些单克隆抗体与临床使用的抗真菌药物组合的体外和体内疗效。