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.

概括：人类巨细胞病毒（CMV）是可能引起的β疱疹病毒家族的成员免疫受损个体的发病率和死亡率。 CMV疾病可以表现为婴儿的神经元缺陷，是影响全世界新生儿的先天缺陷的主要原因。抗病毒药物（例如Ganciclovir和Fomivirsen）已被批准为抗CMV药物。但是，这些药物的局限性包括口服生物利用度较差，剂量相关毒性和选择耐药性病毒突变体以及用于孕妇使用的抗药性。这本应用的主要目的是使用生物制剂抑制CMV感染和传播。我们计划开发和广泛特征由于其中和CMV人类单克隆抗体（mAb）作为未来治疗剂的中和在人类中给药时病毒因素的特异性及其安全性。 CMV的能力感染多种细胞类型，例如成纤维细胞和内皮，上皮和髓样细胞是对于宿主内的病毒传播和增殖至关重要。我们假设一个使用广泛中和针对包膜蛋白的CMV mAb的组合方法将为有效的治疗剂提供抑制CMV进入和传播的基础。我们的初步数据和表征反GH mAb的发现的发现证明了我们的免疫和筛查策略的有效性和特异性，以广泛识别中和CMV mAb。因此，我们将评估我们的假设，并通过完成以下目的：目标1：确定对病毒信封的中和CMV mabs 蛋白质。将使用CMV高通量感染测定法来识别人类单位用完整的临床CMV菌株免疫的速丝菌小鼠。目标2：表征广泛中和抑制感染和传播的CMV mAB。我们计划识别和表征从速丝小鼠鉴定的CMV mABS广泛中和mAb 该功能是预防性和治疗剂。目标3：定义行动机理 CMV中和靶向不同包膜蛋白的mAb。我们计划定义抑制广泛中和mAb的机制，以识别可符合生物学的病毒进入的步骤干涉。目标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mAb处理，以防止基于细胞的病毒传播，器官和动物模型。我们希望优化基于人类MAB的治疗治疗抑制CMV感染和传播作为一种预防和治疗策略适用于高危患者用于CMV相关疾病。