Oral Immunotherapy with IgA to Treat C. difficile Infection

IgA 口服免疫疗法治疗艰难梭菌感染

• 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
• 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

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 梭状芽胞杆菌艰难梭菌感染，是抗生素相关的原因 伪内膜结肠炎是一个日益严重的国家健康问题。发病率 住院美国人口的艰难梭菌感染的原发性杆菌> 30万 每年案件。复发的发生率很高。由于这些原因 迫切需要新的基于非抗生素的治疗方法来治疗这一点 潜在的威胁生命的疾病。提出的新型治疗方法 该应用是一种口服的免疫疗法，由多克隆组成 人类单体和分泌IgA（SIGA）由创新技术形成 将血浆衍生二聚体IgA与重组人相结合的过程 分泌组件。这种创新的免疫疗法将提供重要的 通过肠胃外施用的被动免疫的临床优势 重组单克隆和多克隆IgG抗体。原理证明是 已确立的。我们已经证明了等离子体衍生的Siga提供了 感染艰难梭菌并用A治疗的仓鼠的生存优势 万古霉素的亚治疗剂量。其他人发现等离子体衍生Siga 在小鼠模型中有效预防艰难梭菌疾病的复发。这 该项目的长期目标是商业化口服管理 半合成人分泌免疫球蛋白A用于治疗艰难梭菌 感染。具体目的是：1）确定口服的最小剂量 管理IgA和SIGA，是一种有效的预防治疗 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周的小鼠毒性模型中导致任何毒性。 3）评估用SIGA治疗前后小鼠的肠道微生物组。 4）确定口服施用的IgA和Siga是否有效 艰难梭菌孢子的挑战开始治疗。 5。评估稳定性 在存储期间，血浆得出的IgA和SIGA。 6：确定是否存在 口服人IgA的全身吸收。 7。建立GLP水平 标准操作程序（SOP），用于产品批次的纯度和标识。 8）将生产方法转移到紧急生物溶液中，合同 开发和制造组织（CDMO）进行扩展。