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

基本信息

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
项目类别：
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

项目摘要

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.

血友病A（HA）是由于因子VIII（FVIII）缺乏或功能障碍引起的出血障碍，这是一个重要的血液凝血蛋白。使用外源性FVIII的替代疗法是治疗的第一线。然而，这种挽救生命疗法的主要临床并发症是中和抗FVIII抗体的发展，被称为抑制剂，它消除了FVIII的生物学活性，并增加了与出血相关的风险 HA患者的发病率和死亡率。抑制剂开发后的当前临床选择是昂贵的（> $ 700,000 每年患者）和某些患者无效。那是预防抑制剂开发的成本效益在患者护理方面，但是目前没有安全有效的预防疗法可以避免抑制剂发展。该应用的总体目的是开发fviii（tolip-fviii）的耐受性形式一种新型免疫疗法，可预防HA抑制剂的发展。该平台技术已开发借助NHLBI支持PI，可以利用我们专有溶血磷脂酰丝氨酸的耐受性特性（Lysops）纳米颗粒。我们观察到与FVIII相关的口服和静脉内（IV）预热当受到自由FVIII挑战时，Lysops有效地降低了幼稚的HA小鼠的抑制剂发展，这表明 FVIII-Lysops（Tolip-FVIII）是FVIII的一种耐受性形式，可以预防抑制剂的发展。作为在FVIII的前20次暴露期间，抑制剂发育的风险要高得多，我们设想这种耐受性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形式（幼崽），以双重预防抑制剂的发展。此外，由于血浆存活的提高，这也可能是所有HA患者的作用更长。在R61阶段，我们建议（1）耐用的开发免疫协议宽容; （2）确定通过进行静脉输液的半衰期和止血效率。 HA小鼠的药代动力学和药效学研究和（3）研究静脉注射的毒性在小鼠和非人类隐私中的tolip-fviii。这些SA提出了可衡量的里程碑，识别最佳免疫/治疗方案，用于耐用耐受性，非内部PK和止血效率以及可接受的安全性概况。作为R33的一部分，在第3年，我们将（1）调查这种TOLIP-FVIII方法是否在HA小鼠中成功的狗可以翻译成HA狗，（2）表征这种耐受性形式的PK/PD ha狗的fviii。已经与国家灵长类中心建立了合作，以调查非人类灵长类动物和北卡罗来纳大学进行HA狗研究的Tolip-FVIII。我们提案一项详细的项目管理计划，并与帝国发现研究所合作项目。成功完成该项目将导致一个新型的免疫疗法平台，以防止抑制剂 HA的发展，还可以为创新的治疗选择奠定基础，并具有广泛的临床潜力，例如预防其他治疗蛋白的免疫原性，改善基因疗法和CRISPR 结果，并治疗自身免疫性状况和过敏。