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: 8302052
• 负责人: Roland K Strong
• 金额: $ 21.31万
• 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 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8302052
• 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. PUBLIC HEALTH RELEVANCE: Allogeneic hematopoietic cell transplantation (HCT) has been used to treat life-threatening non-malignant disorders (marrow failure syndromes, hemoglobinopathies and other inherited diseases of the hematopoietic and immune systems), but acute and chronic graft-versus-host disease (GVHD) remain major causes of treatment failure after HCT. We propose to develop computationally-redesigned molecules (receptor-selective versions of B7.1 and B7.2) as short-term immunotherapeutics to promote immune tolerance without compromising immune competence, by targeting the costimulatory receptors CD28 and CTLA-4 and manipulating their signaling outputs. In the long term, this approach could also benefit patients with autoimmune diseases and those undergoing solid organ transplantation; in addition, it would set the stage for combined transplantations of hematopoietic and solid organ grafts, thereby eliminating the need for life-long immunosuppressive treatment in solid organ graft recipients.

描述（由申请人提供）：同种异体造血细胞移植（HCT）是一种有效的治疗危及生命的，非恶性的造血和免疫系统疾病，如骨髓衰竭综合征，血红蛋白病，免疫缺陷疾病和溶酶体贮积病。同种异体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）和供体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），这两种反应都可能是致命的。为了避免移植物排斥和GVHD的问题，异基因HCT受者通常联合使用免疫抑制剂治疗较长时间。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——并且在控制GVHD方面并不总是成功的。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的预后。CD28和CTLA-4是白细胞表面共刺激受体，深刻影响免疫反应的过程：CD28放大TCR信号的作用，增强细胞周期进展和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的工程拮抗剂和激动剂特异性的