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

• 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
• 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' 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

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(申请人提供)：异基因造血细胞移植(HCT)是一种有效的治疗危及生命的非恶性造血和免疫系统疾病，如骨髓衰竭综合征，血红蛋白疾病，免疫缺陷疾病和溶酶体储存疾病。异基因HCT在非恶性疾病患者中的主要局限性是宿主抗移植物反应(移植物排斥反应)和供者淋巴细胞对宿主抗原的免疫反应，也称为移植物抗宿主病(GVHD)，这两者都可能是致命的。为了避免移植物排斥反应和移植物抗宿主病的问题，异基因血细胞移植的受者通常在较长的时间内接受免疫抑制药物的联合治疗。然而，长期的免疫抑制也会削弱宿主对病原体的免疫反应，从而增加严重感染的风险--而且在控制GVHD方面并不是一致成功的。因此，需要努力在不损害免疫能力的情况下促进免疫耐受，以改善HCT的结局。CD28和CTLA-4是白细胞表面的共刺激受体，它们深刻影响免疫应答的过程：CD28放大TCR信号的作用，促进细胞周期进展和T细胞存活；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合理设计的拮抗剂和激动剂 CD28或CTLA-4在不同的临床环境中用作短期免疫疗法，最初侧重于控制异基因HCT后宿主对移植物的反应和GVHD。我们的假设是，移植后不久给予CD28拮抗剂和CTLA-4激动剂，应该会导致宿主和供者T细胞的下调，这些T细胞是针对不匹配的主要和次要抗原而被特异性激活的，阻止了新激活的T细胞的募集并诱导其凋亡。理想的试剂应该对CD28或CTLA-4有最大的选择性，具有较短的生物半衰期以减少免疫相关的不良反应，并具有最小的分子量以最大限度地提高组织穿透性。该项目(R21应用)的探索/开发阶段的直接目标是通过计算将B7.1和B7.2的可溶性形式重新设计成受体特异性结合试剂，通过生化方法确认它们的特性，接下来将在体外细胞分析和体内研究(组织相容骨髓移植的犬模型)中对其进行评估。这些试剂的小尺寸优化了组织渗透率和较短的生物半衰期；我们预测单体形式将作为竞争性拮抗剂和 多聚体(二聚体FC融合或四价试剂)将作为激动剂。这种方法利用了我们成功建立的迭代蛋白质工程流水线，用于开发基于新的B7重新设计靶点的独特治疗应用的计算设计的艾滋病疫苗免疫原(“表位-支架”)。