Therapeutic Antibody for CMV

摘要 人类巨细胞病毒(Hcmv)是引起骨相关内科并发症的主要病毒原因。 骨髓和器官移植。约15%的死产与从母亲到胎儿的病毒传播有关 在美国，每年约有1.6万名出生缺陷。人免疫球蛋白(HIG)被动免疫 在这两个指征上都显示出有希望的活动。HIG是一种复杂的、可变的产品，可能会引起副作用 从非靶标抗体结合。与HIG相比，单抗具有质量上的优势，包括 效力、安全性、生产效率和质量控制。格子生物科学发现了一种高亲和力 针对人巨细胞病毒病毒粒子上最保守的部位(GB AD-2部位I)的天然人源单抗(TRL345)。该单抗 中和了15个不同血清型的临床分离株中的15个。它保护了所有特化的细胞类型 与人类病理学有关。在人体胎盘组织生长的模型中，它也具有完全的保护作用 外植体体外培养。这项已出版的工作是在第一阶段/第二阶段SBIR赠款下完成的。一个主细胞库拥有 已经开发出在CHO细胞中以商业有用的水平(1.5g/L)在50L处表达TRL345 发酵罐秤。几乎所有支持IND的分析工作都已完成，包括大鼠的GLP毒理学 和组织反应性分析。我们现在正在寻求CRP的资金，用于在GMP和 用于第一阶段和第二阶段人体临床试验的制造材料。我们预计将在年内启动第一阶段试验 资助后6个月，并在18个月内完成第二阶段试验。非赠款资金将用于实际的 临床试验费用和超过赠款资助水平的制造成本。以支持可能的 从最初的移植指征延伸到母婴传播指征，我们提出了一种非移植指征 拨款第三年的临床实验和调控策略计划。

Abstract Human cytomegalovirus (HCMV) is the major viral cause of medical complications associated with bone marrow and organ transplantation. Viral transmission from mother to fetus is implicated in ~15% of stillbirths and ~16,000 birth defects annually in the US. Passive immunization using 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). This mAb neutralized 15 out of 15 clinical isolates of diverse serotypes. It protected all of the specialized cell types relevant to human pathology. It was also fully protective in a model of the human placenta 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 (1.5 g/L) at the 50L fermentor scale. Nearly all IND-enabling analytical work has been completed, including GLP toxicology in rats and tissue reactivity profiling. We now seek CRP funding for developing manufacturing under GMP and for manufacturing material for Phase 1 and 2 human clinical trials. We anticipate initiation of a Phase 1 trial within 6 months after funding, and of a Phase 2 trial within 18 months. Non-grant funding will be used for the actual clinical trial expenses and for manufacturing costs beyond the grant funding level. To support possible extension from the initial transplant indication to the maternal-fetal transmission indication, we propose a non- clinical experimental and regulatory strategy program in year 3 of the grant.