B7-based, CD28 or CTLA-4-specific agonists and antagonists for tolerance inductio

基于 B7 的 CD28 或 CTLA-4 特异性激动剂和拮抗剂，用于耐受诱导

基本信息

批准号：
8432007
负责人：
Roland K Strong
金额：
$ 25.64万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
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：
2012-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8432007
关键词：
AIDS Vaccines AIDS vaccine development Acute Acute Graft Versus Host Disease Address Adverse event Affinity Agonist Allogenic Antibodies Antigens Aplastic Anemia Apoptosis Autoimmune Diseases Binding Biochemical Biological Biological Assay Bone Marrow Transplantation CD28 gene CD80 gene Canis familiaris Cell Cycle Progression Cell Survival Cell surface Cells Chimeric Proteins Clinical Competence Cyclosporins Cytotoxic T-Lymphocyte-Associated Protein 4 Development Disease Down-Regulation Engineering Epitopes Failure Fanconi&apos s Anemia Goals Graft Rejection HLA Antigens Half-Life Hematological Disease Hematopoietic Hematopoietic System Hemoglobinopathies Host vs Graft Reaction Human Immune Immune Tolerance Immune response Immune system Immunoglobulin Class Switching Immunoglobulins Immunologic Deficiency Syndromes Immunosuppression Immunosuppressive Agents Immunotherapeutic agent In Vitro Infection Inherited Lead Left Leukocytes Life Ligands Lymphocyte Lysosomal Storage Diseases Marrow Methods Methotrexate Minor Modality Modeling Molecular Weight Mus Non-Malignant Normal Cell Opportunistic Infections Organ Transplantation Orthologous Gene Outcome Output Patients Penetrance Phase Property Protein Engineering Proteins Reaction Reagent Recombinants Regimen Risk Sickle Cell Anemia Signal Transduction Solid Solubility Staging Structure Structure of germinal center of lymph node Supportive care Survival Rate Syndrome T-Cell Proliferation T-Lymphocyte Therapeutic Time Tissues Transplantation Treatment Failure Variant base cancer therapy chronic graft versus host disease clinical practice conditioning design disorder prevention effective therapy graft vs host disease hematopoietic cell transplantation immune function improved in vivo mycophenolate mofetil novel pathogen prevent receptor research study response scaffold

项目摘要

DESCRIPTION (provided by applicant): Allogeneic hematopoietic cell transplantation (HCT) is an effective therapy for life-threatening, non-malignant disorders of the hematopoietic and immune systems, such as marrow failure syndromes, hemoglobinopathies, immunodeficiency disorders and lysosomal storage diseases. Major limitations of allogeneic HCT in patients with nonmalignant disorders have been host-versus-graft reactions (graft rejection) and immune reactions of donor lymphocytes against host antigens, also called graft-versus-host disease (GVHD), both of which can be fatal. To circumvent the problems of graft rejection and GVHD, allogeneic HCT recipients are generally treated with combinations of immunosuppressive agents for extended periods of time. Long term immunosuppression, however, also weakens host immune responses to pathogens, thereby increasing the risk of serious infections - and is not uniformly successful in controlling GVHD. Therefore, efforts at promoting immune tolerance without compromising immune competence are needed to improve outcomes in HCT. CD28 and CTLA-4 are leukocyte cell-surface costimulatory receptors that profoundly influence the course of immune responses: CD28 magnifies the effects of TCR signaling and enhances both cell cycle progression and T cell survival; CTLA-4 (CD152) provides opposing inhibitory signals. CD28 and CTLA-4 bind the shared, related ligands B7.1 (CD80) and B7.2 (CD86). The long-term goal of this project is to develop rationally engineered antagonists and agonists specific for CD28 or CTLA-4 for use as short-term immunotherapeutics in various clinical contexts, initially focusing on the control of host-versus-graft reactions and GVHD following allogeneic HCT. Our hypothesis is that administering a CD28 antagonist along with a CTLA-4 agonist shortly after transplantation should lead to down-regulation of both host and donor T cells that were specifically activated in response to mismatched major and minor antigens, prevent recruitment and induce apoptosis in newly activated T cells. Ideal reagents would be maximally selective for CD28 or CTLA-4, have short biological half-lives to reduce immune related adverse events and minimal molecular weights to maximize tissue penetrance. The immediate goal of the exploratory/developmental phase of this project (this R21 application) is to computationally redesign soluble forms of B7.1 and B7.2 into receptor-specific binding reagents, confirming their properties biochemically, that would next be evaluated in in vitro cell-based assays and in vivo studies (in the canine model of histocompatible marrow transplantation) in subsequent collaborative applications. The small size of these reagents optimizes tissue penetrance and short biological half-life; we predict that monomeric forms will act as competitive antagonists and that multimeric (dimeric Fc fusions or tetravalent reagents) will act as agonists. This approach leverages an iterative protein engineering pipeline we successfully established for the development of computationally-designed AIDS vaccine immunogens ("epitope-scaffolds") for a distinct therapeutic application based on novel B7 redesign targets.

描述（由申请人提供）：同种异性造血细胞移植（HCT）是一种有效的造血和免疫系统的威胁生命的，非恶性疾病的疗法，例如骨髓衰竭综合征，血液型病，免疫缺陷型疾病，免疫缺陷障碍，免疫缺陷疾病和溶血症。非恶性疾病患者的同种异体HCT的主要局限性是宿主 - 移植反应（移植排斥反应）和对宿主抗原的供体淋巴细胞的免疫反应，也称为GRAFT抗原抗原（GVHD），这两种疾病都可能是致命的。为了避免移植排斥和GVHD的问题，通常会长时间用免疫抑制剂的组合对同种异体HCT接受者进行治疗。但是，长期免疫抑制也削弱了宿主对病原体的免疫反应，从而增加了严重感染的风险 - 并且在控制GVHD方面并不统一。因此，需要在不损害免疫能力的情况下促进免疫耐受的努力以改善HCT的预后。 CD28和CTLA-4是白细胞细胞表面的共刺激受体，深远影响免疫反应的过程：CD28放大了TCR信号的影响，并增强了细胞周期的进展和T细胞的存活； CTLA-4（CD152）提供相反的抑制信号。 CD28和CTLA-4结合共享的相关配体B7.1（CD80）和B7.2（CD86）。该项目的长期目标是开发特定于合理设计的对手和激动剂在各种临床环境中，CD28或CTLA-4用作短期免疫治疗药，最初着重于同种异体HCT后的宿主 - 移植反应和GVHD的控制。我们的假设是，在移植后不久，对CD28拮抗剂以及CTLA-4激动剂以及CTLA-4激动剂，应导致宿主和供体T细胞的下调，这些宿主和供体T细胞因响应不匹配的主要和次要抗原而被特异性地激活，防止新激活的T细胞中募集并诱导招募。对于CD28或CTLA-4，理想的试剂将具有最大的选择性，具有短的生物半衰期，可减少与免疫相关的不良事件和最小的分子量，以最大程度地提高组织渗透率。该项目的探索/发育阶段的直接目标（该R21应用）是在计算上重新设计B7.1和B7.2的可溶性形式，以受体特异性的结合试剂为特定的结合试剂，从而在基于体外的细胞和式横向术中对其性质进行了生化的特性，从而对其性质进行了评估申请。这些试剂的小尺寸优化了组织的渗透性和短生物学半衰期。我们预测，单体形式将充当竞争性对手，并且该多聚体（二聚体FC融合或四含量试剂）将充当激动剂。这种方法利用了我们成功建立的迭代蛋白工程管道，用于开发计算设计的艾滋病疫苗免疫原子（“表位 - 损坏”），以基于新颖的B7重新设计目标的独特治疗应用。