Oral Immunotherapy with IgA to Treat C. difficile Infection

IgA 口服免疫疗法治疗艰难梭菌感染

基本信息

批准号：
10609529
负责人：
Michael R Simon
金额：
$ 102.05万
依托单位：
SECRETORY IGA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-14 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10609529
关键词：
2019-nCoV Abdominal Pain Aftercare Agreement Animals Anion Exchange Resins Antibiotics Antibodies Antibody Therapy Bacteria Bacterial Infections COVID-19 Cessation of life Clinical Clostridium difficile Colitis Communicable Diseases Contracts Cost of Illness Data Development Diarrhea Disease Dose Fever Food Hypersensitivity Freeze Drying Freezing Gamma globulin Goals Hamsters Health Health Care Costs Health care facility Hospitalization Human Human Microbiome IgA Deficiency Immunoglobulin A Immunoglobulin G Immunotherapy Incidence Infection Ingestion Inpatients Intestines Journals Life Liquid substance Mediation Methods Mission Modeling Mus Oral Administration Oral cavity Outcome Passive Immunization Paste substance Patients Peer Review Pharmacologic Substance Phase Plasma Population Procedures Process Production Prophylactic treatment Published Comment Publishing Recombinants Recovery Recurrence Relapse Reproduction spores Research Secretory Component Secretory Immunoglobulin A Signs and Symptoms Source Surveys Temperature Therapeutic Therapeutic Agents Toxic effect Toxin United States National Institutes of Health Vancomycin Work absorption combat commercialization cost dimer disability enteric infection experimental study gut microbiome human disease innovation manufacture manufacturing organization member monomer mouse model novel novel therapeutic intervention oral immunotherapy parenteral administration prevent prophylactic relapse prevention safety study scale up treatment choice

项目摘要

Abstract Clostridioides difficile infection, the cause of antibiotic-associated pseudomembraneous colitis, is a growing national health problem. The incidence of primary C. difficile-infection in the hospitalized U.S. population is >300,000 cases annually. There is a high incidence of relapse. For these reasons there is an urgent need for new non-antibiotic based therapeutic approaches to treat this potentially life threatening disease. The novel therapeutic approach proposed in this application is an orally administered immunotherapy consisting of polyclonal human monomeric and secretory IgA (sIgA) formed by the innovative technical process of combining plasma derived dimeric IgA with recombinant human secretory component. This innovative immunotherapy will provide a significant clinical advantage over passive immunization with parenterally administered recombinant monoclonal and polyclonal IgG antibodies. Proof of Principle is established. We have demonstrated that plasma derived sIgA provides a survival advantage to hamsters infected with C. difficile and treated with a subtherapeutic dose of vancomycin. Others have found that plasma derived sIgA was effective in preventing relapse of C. difficile disease in a mouse model. The long-term goal of this project is to commercialize orally administered semisynthetic human secretory immunoglobulin A for the treatment of C. difficile infection. The Specific Aims are: 1) Determine the minimal dose of orally administered IgA and sIgA that is an effective prophylactic treatment in the hamster model of C. difficile disease. 2) Determine whether orally administered human IgA- sIgA mixture results in any toxicity in a 2 week mouse toxicity model. 3) Assess the intestinal microbiome of mice before and after treatment with sIgA. 4) Determine whether orally administered IgA and sIgA is effective when treatment begins after the C. difficile spore challenge. 5. Evaluate the stability of plasma derived IgA and sIgA during storage. 6: Determine whether there is systemic absorption of orally administered human IgA. 7. Establish GLP level Standard Operating Procedures (SOP) for purity and identity of product batches. and 8) Transfer production methods to Emergent BioSolutions, a contract development and manufacturing organization (CDMO) for scale-up.

抽象的艰难梭菌感染，抗生素相关的病因伪膜性结肠炎是一个日益严重的国民健康问题。发病率美国住院人口中原发性艰难梭菌感染率 > 300,000 每年都有案例。复发率很高。由于这些原因有迫切需要新的非抗生素治疗方法来治疗这种疾病可能危及生命的疾病。提出的新治疗方法该应用程序是一种口服免疫疗法，由多克隆抗体组成采用创新技术形成的人类单体和分泌型 IgA (sIgA) 将血浆来源的二聚体 IgA 与重组人结合的过程分泌成分。这种创新的免疫疗法将提供重要的与肠外给药被动免疫相比的临床优势重组单克隆和多克隆 IgG 抗体。原理证明是已确立的。我们已经证明血浆衍生的 sIgA 可以提供感染艰难梭菌并接受过治疗的仓鼠具有生存优势万古霉素的亚治疗剂量。其他人发现血浆衍生的 sIgA 在小鼠模型中可有效预防艰难梭菌疾病的复发。这该项目的长期目标是将口服给药商业化用于治疗艰难梭菌的半合成人分泌型免疫球蛋白 A 感染。具体目标是： 1) 确定口服的最小剂量给予 IgA 和 sIgA，这是一种有效的预防性治疗艰难梭菌疾病的仓鼠模型。 2) 确定是否口服人 IgA-sIgA 混合物在 2 周小鼠毒性模型中会产生任何毒性。 3) 评估sIgA治疗前后小鼠肠道微生物群。 4) 确定口服IgA和sIgA是否有效艰难梭菌孢子攻击后开始治疗。 5. 评估稳定性储存期间血浆衍生的 IgA 和 sIgA。 6：判断是否有口服人 IgA 的全身吸收。 7. 建立GLP水平产品批次纯度和特性的标准操作程序 (SOP)。 8) 将生产方法转移给 Emergent BioSolutions，签订合同用于扩大规模的开发和制造组织（CDMO）。