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Human CMV monoclonal antibodies as therapeutics to inhibit virus infection and dissemination

人 CMV 单克隆抗体作为抑制病毒感染和传播的治疗药物

基本信息

批准号：
10867639
负责人：
Domenico Tortorella
金额：
$ 68.39万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2023-07-19 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10867639
关键词：
Acquired Immunodeficiency Syndrome Affect Affinity Animal Model Antibodies Antibody Therapy Antiviral Agents Autoimmune Diseases B-Lymphocytes Benign Binding Biochemical Biological Biological Assay Biological Availability Biological Models Biological Products Blood Vessels CD14 gene CD34 gene Capsid Cardiovascular Diseases Cell membrane Cell surface Cells Cellular Membrane Cercopithecine Herpesvirus 1 Cholesterol Clinical Clinical Trials Combined Modality Therapy Complementary DNA Complex Congenital Abnormality Cytomegalovirus Cytomegalovirus Infections Cytosol Data Defect Development Disease Dose Effectiveness Endosomes Endothelial Cells Epithelial Cells Escape Mutant Event Family Fibroblasts Foundations Future Ganciclovir Gastrointestinal Diseases Generations Herpesviridae Human Immunization Immunize Immunocompetent Immunocompromised Host Individual Infant Infection Intervention Link Macrophage Membrane Microdomains Modeling Monoclonal Antibodies Morbidity - disease rate Mus Myeloid Cells Neurons Newborn Infant Oral Organ Organoids Patients Pharmaceutical Preparations Pharmacologic Substance Phase Pneumonia Pregnant Women Primary Infection Production Proliferating Proteins Proteomics Publishing Risk Safety Specificity Syndrome Therapeutic Therapeutic Agents Toxic effect Transgenic Mice Transplant Recipients Transplantation Tropism Vascular Endothelium Viral Viral Envelope Proteins Viral Physiology Virus Virus Diseases cell type combinatorial congenital cytomegalovirus drug resistant virus env Gene Products fomivirsen high risk human monoclonal antibodies in vivo inhibiting antibody maribavir member monocyte mortality mutant neutralizing monoclonal antibodies prevent prophylactic receptor binding screening therapeutically effective

项目摘要

Summary: Human cytomegalovirus (CMV) is a member of the beta herpesvirus family that can cause morbidity and mortality in immuno-compromised individuals. CMV disease can manifest as neuronal defects in infants and is the leading cause of birth defects affecting newborns worldwide. Anti-viral drugs such as ganciclovir and fomivirsen have been approved as anti-CMV drugs. However, these drugs have limitations including poor oral bioavailability, dose-related toxicity and selection of drug resistant viral mutants as well as precluded for use in pregnant women. The main objective of this application is to optimize prophylactic and therapeutic conditions using biologics to inhibit CMV infection and dissemination. We plan to develop and characterize broadly neutralizing CMV human monoclonal antibodies (mAbs) as future therapeutics due to its specificity for viral factors and its safety profile when administered in humans. The ability of CMV to infect multiple cell types such as fibroblasts and endothelial, epithelial, and myeloid cells is essential for viral dissemination and proliferation within the host. We hypothesize that a combinatorial approach using broadly neutralizing CMV mAbs against envelope proteins will provide the basis for effective therapeutics to inhibit CMV entry and dissemination. Our preliminary data and published findings characterizing anti-gH mAbs have demonstrated the effectiveness and specificity of our immunization and screening strategies to identify broadly neutralizing CMV mAbs. Thus, we will evaluate our hypothesis and accomplish our objective by completing the following aims: Aim 1: Identify neutralizing CMV mAbs against viral envelope proteins. A CMV high-throughput infection assay will be employed to identify human mAbs from VelocImmuneTM mice immunized with intact clinical CMV strains. Aim 2: Characterization of broadly neutralizing CMV mAbs that inhibit infection and dissemination. We plan to identify and characterize the CMV mAbs identified from VelocImmuneTM mice as broadly neutralizing mAbs that function as prophylactic and therapeutic agents. Aim 3: Define the mechanism of action of CMV neutralizing mAbs targeting different envelope proteins. We plan to define the inhibitory mechanism of broadly neutralizing mAbs to identify the steps of virus entry amenable to biologic intervention. Aim 4: Determine therapeutic conditions to prevent dissemination in diverse models. We plan to determine the optimal mAb treatment to prevent virus dissemination in cell-based, organoid, and animal models. We expect to optimize human mAb-based therapeutic treatments to inhibit CMV infection and dissemination as a prophylactic and therapeutic strategy to be utilized for patients at high-risk for CMV-associated disorders.

总结：人巨细胞病毒（CMV）是β疱疹病毒家族的一员，可引起免疫功能低下个体的发病率和死亡率。CMV疾病可以表现为婴儿神经元缺陷，并且是影响全世界新生儿的出生缺陷的主要原因。抗病毒药物如更昔洛韦和福米韦生已被批准为抗CMV药物。然而，这些药物具有局限性，包括口服生物利用度差、剂量相关毒性和选择耐药病毒突变体以及排除用于孕妇。的本申请的主要目的是优化预防和治疗条件，抑制CMV感染和传播的生物制剂。我们计划开发和表征广泛的中和CMV人单克隆抗体（mAb）作为未来的治疗剂，其对病毒因子的特异性和在人体中施用时的安全性特征。CMV的能力感染多种细胞类型，如成纤维细胞和内皮细胞、上皮细胞和骨髓细胞，对病毒在宿主体内的传播和增殖至关重要。我们假设使用针对包膜蛋白的广泛中和CMV mAb的组合方法将为抑制CMV进入和传播的有效治疗提供基础。我们表征抗gH mAb的初步数据和已发表的研究结果表明，我们的免疫接种和筛查策略的有效性和特异性，中和CMV mAb。因此，我们将评估我们的假设，并实现我们的目标，完成以下目标：目标1：鉴定针对病毒包膜的中和CMV mAb proteins.将采用CMV高通量感染测定法来鉴定人mAb，用完整临床CMV毒株免疫的VelocImmuneTM小鼠。目标2：表征抑制感染和传播的广泛中和CMV mAb。我们计划识别和将从VelocImmuneTM小鼠中鉴定的CMV mAb表征为广泛中和mAb 作为预防和治疗剂。目标3：确定靶向不同包膜蛋白的CMV中和mAb。我们计划定义抑制性广泛中和mAb的机制，以确定病毒进入的步骤，干预目的4：确定治疗条件，以防止在不同模型中传播。我们计划确定最佳的单克隆抗体治疗，以防止病毒传播的细胞为基础，类器官和动物模型。我们希望优化基于人类单克隆抗体的治疗方法，抑制CMV感染和传播作为一种预防和治疗策略，对于CMV相关疾病的高风险患者。