Combined Factor VIII Replacement and Tolerance Therapy for Hemophilia A

A 型血友病联合因子 VIII 替代和耐受治疗

基本信息

批准号：
8508305
负责人：
Anne Searls DeGroot
金额：
$ 37.64万
依托单位：
EPIVAX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8508305
关键词：
Antibody Formation Antigen Presentation Antigen Targeting Binding Biological Markers Blocking Antibodies Blood Coagulation Factor Cell Line Cells Chemicals Clinical Research Clinical Trials Clinical Trials Design Coagulation Process Collaborations Complex Disease Dose Drug Formulations Endogenous Factors Engineering Enzyme-Linked Immunosorbent Assay Epitopes Evaluation Factor VIII Fermentation Flow Cytometry Future Goals Half-Life Health Health Sciences Hemophilia A Hemorrhage Human Immune Tolerance Immune response Immune system Immunoglobulins Immunologist Immunology Immunosuppressive Agents In Vitro Incidence Infection Inflammation Infusion procedures Intervention Knockout Mice Ligands Link Liquid substance Mass Spectrum Analysis Measures Mediating Methods Modeling Monitor Mus Neoadjuvant Therapy Outcome Pathway interactions Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Phenotype Positioning Attribute Prevention Process Production Proteins Protocols documentation Publications Recombinants Regulatory T-Lymphocyte Replacement Therapy Research Risk Running Saline Services Small Business Innovation Research Grant Surface Antigens T cell response T-Lymphocyte Target Populations Testing Therapeutic Thrombosis Universities Work chemical conjugate cost effective cytokine drug development experience gel electrophoresis human F8 protein immune function immunogenicity immunoregulation in vivo inhibitor/antagonist interest neutralizing antibody novel phase 2 study programs response

项目摘要

DESCRIPTION (provided by applicant): The goal of this new SBIR program is to produce a combined clotting Factor VIII replacement and immunomodulatory therapy that will provide FVIII-specific tolerance induction at therapeutic doses for Hemophilia A patients. Hemophiliacs with <1% functional FVIII are classified as severe and must receive regular doses of replacement factor. A major issue with successful FVIII replacement therapy for Hemophilia A is overcoming the neutralizing antibody response against FVIII that is seen in up to 30% of hemophiliacs and 50% of patients with severe disease. These "inhibitors" delay or inhibit clotting by interfering with FVIII binding to its ligands. A number of treatments for inhibitors exist but these approaches are either not fully successful or still experimental and present a large health risk for the patient. There is an urgent need for a safe, biologically rational and cost effective approach to induce long-term immune tolerance to FVIII. "Tregitopes" are immunoglobulin-derived natural regulatory T-cell (nTreg) epitopes that expand a subset of circulating nTregs, leading to suppression of inflammation and, when administered with a target antigen, adaptive tolerance. Since publication of this discovery in 2008, we have shown that presentation of Tregitopes at the surface of antigen presentation cells (APCs) to nTregs drives tolerogenic pathways in both APCs and nTregs, and induces target-antigen specific adaptive Tregs that interface with the same APC. Thus, as a natural immune system 'off switch,' Tregitopes have great potential as therapeutics to induce immunological tolerance to co-administered proteins. We therefore propose to couple Tregitopes to FVIII to produce a novel combined replacement and tolerance induction therapy. In this Phase I proof-of concept application, we propose to (i) demonstrate that FVIII-Tregitope modulates human T cell responses and establish correlates of tolerance induction that may be used in clinical trial design and (ii) demonstrate FVIII-Tregitope-mediated tolerance induction in an in vivo hemophilia model, which enables evaluation of Tregitope efficacy on the key outcome - elimination of inhibitors. In future Phase II studies, we will transition to recombinant production of FVIII-Tregitope, a process too complex and costly for proof-of-concept studies. ProBioGen, our Phase II collaborator, is a leading company with expertise in activities central to the manufacture of recombinant human FVIII, including cell line engineering, upstream fermentation, downstream purification, liquid pre-formulation of bulk drug substance and in-process analytics including titer determination and chromogenic determination of FVIII bioactivity. In addition, we have established a strong collaboration with a large Pharma that has experience in the regulatory and clinical trial aspects of FVIII drug development and anticipate that FVIII-Tregitope will move into clinical studies once we achieve the goals of the SBIR program.

描述（由申请人提供）：这个新的 SBIR 项目的目标是生产一种联合凝血因子 VIII 替代和免疫调节疗法，为血友病 A 患者提供治疗剂量的 FVIII 特异性耐受诱导。功能性 FVIII <1% 的血友病患者被归类为严重血友病患者，必须接受定期剂量的替代因子。成功使用 FVIII 替代疗法治疗 A 型血友病的一个主要问题是克服针对 FVIII 的中和抗体反应，这种反应出现在高达 30% 的血友病患者和 50% 的重症患者中。这些“抑制剂”通过干扰 FVIII 与其配体的结合来延迟或抑制凝血。存在许多针对抑制剂的治疗方法，但这些方法要么没有完全成功，要么仍处于试验阶段，并且给患者带来了巨大的健康风险。迫切需要一种安全、生物学合理且具有成本效益的方法来诱导对 FVIII 的长期免疫耐受。 “Treg位”是免疫球蛋白衍生的天然调节性T细胞(nTreg)表位，其扩展循环nTreg的子集，从而抑制炎症，并且当与靶抗原一起施用时，产生适应性耐受。自 2008 年发表这一发现以来，我们已经证明，抗原呈递细胞 (APC) 表面的 Tregitope 向 nTreg 的呈递可驱动 APC 和 nTreg 中的耐受性途径，并诱导与同一 APC 相互作用的靶标抗原特异性适应性 Tregs 。因此，作为天然免疫系统的“关闭开关”，Tregitopes 具有作为诱导对共同施用的蛋白质的免疫耐受性的治疗剂的巨大潜力。因此，我们建议将 Tregitopes 与 FVIII 结合以产生一种新型的联合替代和耐受诱导疗法。在此 I 期概念验证申请中，我们建议 (i) 证明 FVIII-Tregitope 调节人类 T 细胞反应并建立可用于临床试验设计的耐受诱导的相关性，以及 (ii) 证明 FVIII-Tregitope 介导的体内血友病模型中的耐受诱导，这使得能够评估 Tregitope 对关键结果（抑制剂消除）的功效。在未来的 II 期研究中，我们将过渡到 FVIII-Tregitope 的重组生产，这一过程对于概念验证研究而言过于复杂且成本高昂。我们的 II 期合作伙伴 ProBioGen 是一家领先的公司，在重组人 FVIII 制造的核心活动方面拥有专业知识，包括细胞系工程、上游发酵、下游纯化、原料药的液体预配制以及包括滴度在内的过程分析FVIII生物活性的测定和显色测定。此外，我们还与一家在 FVIII 药物开发的监管和临床试验方面拥有经验的大型制药公司建立了强有力的合作，并预计一旦我们实现 SBIR 计划的目标，FVIII-Tregitope 将进入临床研究。