HCMV Therapeutic Antibody Safety Trial

摘要 人巨细胞病毒（HCMV）从母亲传播给胎儿涉及约15%的死产， 美国每年约有16，000例出生缺陷。巨细胞病毒也是导致医学并发症的主要病毒原因， 进行骨髓和器官移植使用抗HCMV富集的人免疫的被动免疫 球蛋白（HIG）对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， 引起脱靶抗体结合的副作用。单克隆抗体（mAb）具有定性优势 包括效价、安全性、生产效率和质量控制。Trellis Bioscience发现 针对HCMV病毒体上最保守位点（gB AD-2位点）的高亲和力天然人mAb（TRL 345） （一）。TRL 345是从人B克隆的人IgG 1 κ（G1 m1，17（z，a）; Km 3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。在人类胎盘模型中， 作为组织外植体离体生长的片段。这一出版工作是在第一/第二阶段SBIR赠款下完成的。 已经开发了在CHO细胞中以商业上有用的水平表达TRL 345的主细胞库 (1.74 g/L）。已完成所有IND启用分析工作，包括GLP毒理学 和组织反应性分析。在SBIR CRP的资助下，第一个临床批次已经生产， 为1期和2期人体临床试验提供充足的材料。我们建议在这里进行第一阶段的单一 在健康志愿者中进行的剂量递增临床试验。

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.