HCMV Therapeutic Antibody Safety Trial

HCMV 治疗性抗体安全性试验

基本信息

批准号：
10015670
负责人：
Lawrence Michael Kauvar
金额：
$ 29.97万
依托单位：
TRELLIS BIOSCIENCE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10015670
关键词：
Adult Affinity Antibodies Antiviral Agents B-Lymphocytes Binding Biological Sciences Bone Marrow Transplantation Child Chinese Hamster Ovary Cell Clinical Clinical Research Clinical Trials Cognitive Communicable Diseases Complex Congenital Abnormality Consultations Cytomegalovirus Delaware Development Disease Documentation Dose Drug Controls Drug Kinetics Epitopes Ethical Review Europe Fetus First Pregnancy Trimester Funding Grant Health Personnel Hospitalization Human Human Cloning Human Pathology Human Resources Immunoglobulins In Vitro Incidence Infection International Intravenous Japan Leadership Mammals Medical Medical Care Costs Modeling Monoclonal Antibodies Mothers Motor National Institute of Allergy and Infectious Disease Organ Organ Transplantation Passive Immunization Patients Phase Phase II Clinical Trials Population Positioning Attribute Pregnancy Private Sector Production Protocols documentation Publishing Quality Control Rattus Reporting Risk Safety Science Serotyping Services Site Small Business Innovation Research Grant Solid Specificity Technology Testing Therapeutic Agents Therapeutic Monoclonal Antibodies Therapeutic antibodies Tissues Toxic effect Toxicology Transplant Recipients Transplantation U-Series Cooperative Agreements Viral Virion Woman Work Writing cell bank cell type clinical development clinical lot cost cross reactivity deafness economic impact first-in-human healthy volunteer human model human monoclonal antibodies interest latent infection lead candidate medical complication neutralizing monoclonal antibodies operation phase I trial polyclonal human antibody prevent programs reactivation from latency side effect small molecule stillbirth transmission process

项目摘要

Abstract Human cytomegalovirus (HCMV) transmission from mother to fetus is implicated in ~15% of stillbirths and ~16,000 birth defects annually in the US. HCMV is also the major viral cause of medical complications associated with bone marrow and organ transplantation. Passive immunization using anti-HCMV enriched human immune globulin (HIG) has shown promising activity for both indications. HIG is a complex, variable product that may cause side effects from off-target antibody binding. A monoclonal antibody (mAb) offers qualitative advantages over HIG including potency, safety, production efficiency and quality control. Trellis Bioscience has discovered a high affinity native human mAb (TRL345) against the most conserved site on the HCMV virion (gB AD-2 Site I). TRL345 is a human IgG1kappa (G1m1,17 (z,a); Km3 allotype) monoclonal antibody cloned from human B lymphocytes. This mAb neutralized 15 out of 15 clinical isolates of all four major serotypes. It protected all of the specialized cell types relevant to human pathology. It was also fully protective in a model of human placental fragments grown as tissue explants ex vivo. This published work was completed under a Phase I/II SBIR grant. A Master Cell Bank has been developed that expresses TRL345 in CHO cells at a commercially useful level (1.74 g/L) at the 250L GMP scale. All IND-enabling analytical work has been completed, including GLP toxicology in rats and tissue reactivity profiling. With SBIR CRP funding, the first clinical lot has been manufactured yielding sufficient material for Phase 1 and 2 human clinical trials. We propose here to conduct a Phase 1 single ascending dose clinical trial in healthy volunteers.

抽象的人类巨细胞病毒 (HCMV) 从母亲传播给胎儿与约 15% 的死产和胎儿有关美国每年约有 16,000 例出生缺陷。 HCMV 也是相关医疗并发症的主要病毒原因与骨髓和器官移植。使用富含抗 HCMV 的人体免疫进行被动免疫球蛋白 (HIG) 对于这两种适应症都显示出有希望的活性。 HIG 是一种复杂、多变的产品，可能导致抗体结合脱靶产生副作用。单克隆抗体 (mAb) 具有质量优势 HIG 的主要内容包括效力、安全性、生产效率和质量控制。 Trellis Bioscience 发现针对 HCMV 病毒颗粒上最保守的位点（gB AD-2 位点）的高亲和力天然人单克隆抗体 (TRL345) 我）。 TRL345 是从人 B 克隆的人 IgG1kappa (G1m1,17 (z,a); Km3 同种异型) 单克隆抗体淋巴细胞。该 mAb 中和了所有四种主要血清型的 15 种临床分离株中的 15 种。它保护了所有与人类病理学相关的特殊细胞类型。它在人类胎盘模型中也具有完全保护作用片段作为组织外植体离体生长。这项发表的工作是在 I/II 期 SBIR 资助下完成的。已开发出主细胞库，可在 CHO 细胞中以商业可用水平表达 TRL345 (1.74 g/L) 在 250L GMP 规模下。所有支持 IND 的分析工作均已完成，包括 GLP 毒理学在大鼠和组织反应性分析中。在 SBIR CRP 的资助下，第一个临床批次已经生产出来为第一阶段和第二阶段人体临床试验提供足够的材料。我们在此建议进行第一阶段单曲在健康志愿者中进行的剂量递增临床试验。