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: 10476775
• 负责人: Stephen C Brown
• 金额: $ 89.23万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10476775
• 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; 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; 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; anti-IgA; base; combat; commercialization; cost; dimer; disability; enteric infection; experimental study; gut microbiome; human disease; innovation; member; mouse model; novel; novel therapeutic intervention; oral immunotherapy; parenteral administration; prevent; prophylactic; 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.

摘要 艰难梭状芽胞杆菌感染与抗生素相关的原因 伪膜性结肠炎，是一个日益严重的全民健康问题。发病率 美国住院人群中原发艰难梭菌感染的风险为30万 每年都有病例。复发率很高。出于这些原因，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。年提出的新的治疗方法 此应用是一种口服免疫疗法，由多克隆组成。 创新技术形成的人类单体分泌型IgA(SIgA) 血源性二聚体IgA与重组人免疫球蛋白结合的研究进展 分泌成分。这种创新的免疫疗法将提供一种重要的 非肠道被动免疫的临床优势 重组单抗和多克隆抗体。原则的证明是 已经成立了。我们已经证明，血浆来源的SIgA提供了一种 感染艰难梭菌的仓鼠的生存优势 亚治疗剂量的万古霉素。其他人发现，血浆来源的SIgA 在小鼠模型中有效地防止艰难梭菌病的复发。这个 该项目的长期目标是将口服药物商业化 半合成人分泌型免疫球蛋白A治疗艰难梭菌 感染。具体目标是：1)确定口服的最小剂量 应用IgA和SIgA是一种有效的预防治疗 艰难梭菌病仓鼠模型。2)确定是否口服 在2周的小鼠毒性模型中，人IgA-SIgA混合物可导致任何毒性。 3)检测SIgA治疗前后小鼠肠道菌群的变化。 4)确定口服IgA和SIgA在以下情况下是否有效 治疗在艰难梭菌孢子挑战后开始。5.评估系统的稳定性 储存过程中血浆来源的IgA和SIgA。6：确定是否有 口服人免疫球蛋白A的全身吸收。7.建立GLP级别 产品批次纯度和特性的标准操作程序(SOP)。 8)将生产方法转让给Emerent BioSolutions，这是一份合同 用于扩大规模的开发和制造组织(CDMO)。