Development of tolerogenic Factor VIII as immunotherapy to prevent inhibitor development in Hemophilia A

开发耐受性因子 VIII 作为免疫疗法来预防 A 型血友病抑制剂的产生

• 批准号: 10594819
• 负责人: SATHY VENKAT BALU-IYER
• 金额: $ 57.55万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-27 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594819
• 关键词: Address; Antibodies; Antibody titer measurement; Autoimmune Diseases; Biological; Blood Coagulation Disorders; Blood coagulation; Canis familiaris; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complication; Development; Exogenous Factors; Factor VIII; Foundations; Functional disorder; Half-Life; Health; Hemophilia A; Hemorrhage; Hemostatic Agents; Human; Hypersensitivity; Immune response; Immunization; Immunotherapy; Intravenous; Investigational Drugs; Knowledge; Laboratories; Life; Lipid Binding; Measurable; Measures; Medical; Mission; Modeling; Morbidity - disease rate; Mus; National Heart, Lung, and Blood Institute; North Carolina; Oral; Outcome; Patient Care; Patients; Pharmaceutical Preparations; Phase; Phosphatidylserines; Plasma; Prevention; Preventive therapy; Primates; Property; Proteins; Protocols documentation; Public Health; Replacement Therapy; Research; Risk; Route; Safety; Study models; Testing; Therapeutic; Toxic effect; Translating; Treatment Protocols; United States National Institutes of Health; Universities; cost; cost effective; efficacy evaluation; gene therapy; high risk; immunogenic; immunogenicity; improved; inhibitor; innovation; intravenous administration; lysophosphatidylserine; mortality; nanoparticle; nonhuman primate; novel; pharmacokinetics and pharmacodynamics; preservation; prevent; recombinant antihemophilic factor VIII; response; success; technology platform; therapeutic protein

Hemophilia A (HA) is a bleeding disorder caused by deficiency or dysfunction of Factor VIII (FVIII), an important blood coagulation protein. The replacement therapy using exogenous FVIII is the first line of therapy. However, a major clinical complication of this life-saving therapy is the development of neutralizing anti-FVIII antibodies, referred to as inhibitors, that abrogates the biological activity of FVIII and increases the risk of bleeding related morbidity and mortality in HA patients. Current clinical options after inhibitor development are costly (>$700,000 per patient annually) and in some patients, ineffective. Thus, prevention of inhibitor development is cost-effective in terms of patient care but there are no safe and effective preventive therapy currently available to avoid inhibitor development. The overall objective of this application is to develop a tolerogenic form of FVIII (TOLIP-FVIII) as a novel immunotherapy to prevent inhibitor development in HA. This platform technology has been developed with NHLBI support to PI that harnesses the tolerogenic property of our proprietary lysophosphatidylserine (lysoPS) nanoparticle. We observed that an oral and intravenous (IV) pre-administration of FVIII associated with lysoPS effectively reduced inhibitor development in naïve HA mice when challenged with free FVIII, suggesting that FVIII-lysoPS (TOLIP-FVIII) is a tolerogenic form of FVIII that could prevent inhibitor development. As the risk of inhibitor development is much higher during the first 20 exposures of FVIII, we envision this tolerogenic form as beginner replacement therapy during high-risk exposure period, for previously untreated patients (PUPs), to durably prevent inhibitor development. Further, due to improved plasma survival, this could also be a longer acting FVIII for all HA patients. In R61 phase, we propose to (1) develop immunization protocol for durable tolerance; (2) determine the half-life and hemostatic efficacy of IV administered TOLIP-FVIII by conducting pharmacokinetic and pharmacodynamic studies in HA mice and (3) to investigate the toxicity of iv administered TOLIP-FVIII in mice and in non-human primates. These SAs present measurable milestones, identification of optimal immunization/treatment protocol for durable tolerance, non-inferior PK and hemostatic efficacy and acceptable safety profile. As part of R33, in year 3, we will (1) investigate whether this TOLIP-FVIII approach that is successful in HA mice can be translated to HA dogs and (2) characterize PK/PD of this tolerogenic form of FVIII in HA dogs. Collaborations have been established with National Primate Center to investigate toxicity of TOLIP-FVIII in non-human primates and with the University of North Carolina to conduct HA dog studies. We propose a detailed project management plan and partnered with Empire Discovery Institute for R33 phase of the project. Successful completion of the project will lead to a novel immunotherapy platform to prevent inhibitor development in HA and could also lay the foundation for innovative therapeutic options with broad clinical potential, such as prevention of immunogenicity of other therapeutic proteins, improve gene therapy and CRISPR outcomes, and treat autoimmune conditions and allergies.

A 型血友病 (HA) 是由因子 VIII (FVIII) 缺乏或功能障碍引起的出血性疾病，因子 VIII (FVIII) 是一种重要的血友病。 凝血蛋白。使用外源性 FVIII 的替代疗法是一线疗法。然而， 这种挽救生命的疗法的一个主要临床并发症是中和性抗 FVIII 抗体的产生， 称为抑制剂，它会消除 FVIII 的生物活性并增加出血相关的风险 HA 患者的发病率和死亡率。目前抑制剂开发后的临床选择成本高昂（> 700,000 美元 每名患者每年），但对某些患者无效。因此，预防抑制剂的发展具有成本效益 在患者护理方面，但目前没有安全有效的预防疗法来避免抑制剂 发展。本申请的总体目标是开发一种耐受性形式的 FVIII (TOLIP-FVIII) 作为 一种预防 HA 抑制剂发展的新型免疫疗法。该平台技术已开发完成 借助 NHLBI 对 PI 的支持，利用我们专有的溶血磷脂酰丝氨酸的耐受性特性 （lysoPS）纳米颗粒。我们观察到，口服和静脉注射 (IV) 预给予 FVIII 与 当受到游离 FVIII 攻击时，lysoPS 有效减少了首次接触的 HA 小鼠中抑制剂的产生，表明 FVIII-lysoPS (TOLIP-FVIII) 是 FVIII 的一种耐受形式，可以阻止抑制剂的产生。作为 在前 20 次暴露于 FVIII 期间，产生抑制剂的风险要高得多，我们预计这种耐受性 对于以前未经治疗的患者，在高风险暴露期间作为初学者替代疗法 （PUP），持久防止抑制剂的发展。此外，由于血浆存活率提高，这也可能是 适用于所有 HA 患者的长效 FVIII。在R61阶段，我们建议（1）制定持久的免疫方案 宽容; (2)通过进行测定IV施用TOLIP-FVIII的半衰期和止血功效 HA 小鼠的药代动力学和药效学研究以及 (3) 研究静脉注射给药的毒性 TOLIP-FVIII 在小鼠和非人类灵长类动物中的作用。这些 SA 提出了可衡量的里程碑，确定了 最佳免疫/治疗方案，可实现持久耐受、不劣质的 PK 和止血功效以及 可接受的安全状况。作为 R33 的一部分，在第 3 年，我们将 (1) 研究这种 TOLIP-FVIII 方法是否 在 HA 小鼠中取得成功的结果可以转化为 HA 狗，并且 (2) 表征这种耐受形式的 PK/PD HA 狗体内的 FVIII。已与国家灵长类动物中心建立合作，研究 TOLIP-FVIII 在非人类灵长类动物中的应用以及与北卡罗来纳大学合作进行的 HA 狗研究。我们 提出详细的项目管理计划，并与 Empire Discovery Institute 合作开展 R33 阶段的项目 项目。该项目的成功完成将产生一个新型的免疫治疗平台来预防抑制剂 HA 的发展也可以为具有广泛临床意义的创新治疗方案奠定基础 潜力，例如预防其他治疗蛋白的免疫原性，改善基因治疗和 CRISPR 结果，并治疗自身免疫性疾病和过敏。