Novel Immunoprophylaxes against Clostridium difficile Infection

针对艰难梭菌感染的新型免疫预防方法

• 批准号: 8652654
• 负责人: Hanping Feng
• 金额: $ 87.87万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8652654
• 关键词: Active Immunization; Acute; Address; Affinity; Aging; Alpaca; Animal Model; Animals; Antibiotic Resistance; Antibiotics; Antibodies; Antibody Formation; Antitoxins; Area; Binding; Cessation of life; Clinical; Clinical Research; Clinical Trials; Clostridium difficile; Colitis; Development Plans; Diarrhea; Discipline; Disease; Dose; Drug Formulations; Effectiveness; Elderly; Ensure; Enteral; Epidemic; Evaluation; Excipients; FDA approved; Family suidae; Fc Immunoglobulins; Funding; Genes; Gnotobiotic; Goals; Half-Life; Hamsters; Human; Immune; Immunization; Immunoglobulin G; In Vitro; Incidence; Individual; Infection; Infection prevention; Intervention; Intestines; Investigation; Lead; Light; Location; Modeling; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mus; Mutagenesis; National Institute of Allergy and Infectious Disease; Oral; Passive Immunization; Patients; Phase; Physiology; Population; Prevention; Recovery; Recurrence; Regimen; Relapse; Reproduction spores; Research; Research Personnel; Serum; Severities; System; Testing; Toxic effect; Toxin; Toxin Conjugates; Translating; United States National Institutes of Health; Vaccination; Vaccines; age group; aged; antigen binding; autoreactivity; controlled release; design; dosage; enteric pathogen; high risk; immunogenicity; immunosenescence; in vivo; manufacturing process; monomer; mortality; mouse model; neutralizing antibody; novel; older patient; preclinical evaluation; prevent; product development; research clinical testing; resistant strain; response; standard care; sugar; young adult

Clostridium difficile infection (CDI) has become a major emerging cause of morbidity and mortality among hospitalized patients since the epidemics of hypervirulent and antibiotic-resistant strains began in the early 2000s. It is therefore important to develop new preventions/treatments to counteract the rapid increase in the incidence of CDI. While standard treatments with antibiotics are not effective resulting in high rates of relapse, animal and clinical studies have unambiguously demonstrated that antitoxin antibodies are protective against both primary and recurrent CDI. Our goal is to develop novel immunoprophylaxes against both primary and recurrent CDI in aged high-risk populations. In this proposal we aim to exploit two novel compounds (ABBA and cTxAB) developed in this lab: 1) ABBA is a single tetra-specific binding agent consisting of four distinct neutralizing VHH monomers (two against TcdA and two against TcdB); and 2) cTxAB is an atoxic, clostridial toxin-like chimeric vaccine for which a product development plan (PDP) toward clinical trials is currently being developed under NIH funding. We have already demonstrated potent efficacy of ABBA against fulminant CDI in mice. We will further optimize and finalize its delivery strategies in this project. To reduce potential immunogenicity and increase the serum half-life of ABBA for systemic administration, we will generate ABBA-Fc fusions and humanized ABBA-lgGIs without compromising its superior affinity to toxins and neutralizing activity. In addition, we will develop a colonic delivery system for intestinal delivery of ABBA. The lead compounds generated for systemic and oral deliveries will be evaluated in a hamster fulminant CDI model as well as in gnotobiotic piglets colonized with human intestinal flora. Moreover, we will combine the passive ABBA immunization with active cTxAB vaccination and evaluate protection against both primary and recurrent CDI in relevant immunosenescent mouse models. Our ultimate goal is to develop novel immunoprophylaxes and combinations of active and passive immunizations that we wish to prevent against both immediate and longer term CDI threats in aged patients with high risk of developing this debilitating disease. This project will help to achieve the broad objective ofthe entire CETR proposal and to address the hypothesis that we can translate promising immunoprophylactic candidate products being tested in relevant immunosenescent animal models into immune preventions against important enteric pathogens for which the ultimate human targets are elderly subjects.

自2000年代初期开始，艰难梭菌感染（CDI）已成为住院患者发病率和死亡率的重大新兴原因和死亡率。因此，重要的是要开发新的预防/治疗方法来抵消CDI发生率的快速增加。虽然具有抗生素的标准治疗无效，导致复发率很高，但动物和临床研究明确证明了抗毒素抗体对原发性和复发性CDI均具有保护作用。我们的目标是在老年高风险人群中开发针对原发性和复发性CDI的新型免疫保险基。在本提案中，我们旨在利用本实验室中开发的两种新型化合物（ABBA和CTXAB）：1）ABBA是一种单个TETRA特异性结合剂，该结合剂由四个不同的中和中和中和的VHH单体组成（两种针对TCDA和两个针对TCDB）； 2）CTXAB是一种毒性，梭状芽胞杆菌毒素样的嵌合疫苗，目前正在根据NIH资金开发产品开发计划（PDP）针对临床试验。我们已经证明了ABBA对小鼠的暴发性CDI的有效功效。我们将进一步优化并最终确定其在该项目中的交付策略。为了降低潜在的免疫原性并增加了全身给药的ABBA血清半衰期，我们将产生ABBA-FC融合和人源化的ABBA-LGGIS，而不会损害其对毒素和中和活性的优势亲和力。此外，我们将开发一个结肠输送系统，用于肠道递送ABBA。用于全身和口服递送生成的铅化合物将在仓鼠暴发的CDI模型以及用人肠菌群定殖的Gnotobiotic Piglet中评估。此外，我们将将被动ABBA免疫与主动CTXAB疫苗接种相结合，并评估相关免疫小鼠模型中针对初级和复发性CDI的保护。我们的最终目标是开发新型的免疫保留剂以及主动和被动免疫的组合，我们希望防止在患有这种令人衰弱的疾病的高风险的老年患者中，以防止直接和长期的CDI威胁。该项目将有助于实现整个CERT的广泛目标，并解决以下假设：我们可以在相关的免疫动物模型中转化有希望的免疫原性候选产物，以针对对最终人类目标的重要肠道病原体进行免疫预防。