Therapeutic Antibody for CMV

摘要 人巨细胞病毒（HCMV）是与骨相关的医疗并发症的主要病毒原因 骨髓和器官移植约15%的死产涉及母亲向胎儿的病毒传播 美国每年约有16，000例出生缺陷。使用人免疫球蛋白（HIG）的被动免疫具有 对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，可能会引起副作用 来自于脱靶抗体结合。单克隆抗体（mAb）提供了优于HIG的定性优势，包括 有效性、安全性、生产效率和质量控制。Trellis Bioscience发现了一种 针对HCMV病毒体上最保守位点（gB AD-2位点I）的天然人mAb（TRL 345）。该mAb 中和了15个不同血清型的临床分离株中的15个。它保护了所有的特化细胞类型 与人类病理学有关。它在人类胎盘组织模型中也具有完全的保护作用 离体外植体。这一出版工作是在第一/第二阶段SBIR赠款下完成的。主细胞库具有 开发了在CHO细胞中以商业上有用的水平（1.5 g/L）在50 L 发酵罐规模几乎所有IND使能分析工作均已完成，包括大鼠GLP毒理学 和组织反应性分析。我们现在寻求CRP资金，用于在GMP下开发生产， 用于1期和2期人体临床试验的生产材料。我们预计在2015年内启动1期试验， 6个月后的资金，并在18个月内的第二阶段试验。非赠款资金将用于实际 临床试验费用和超出赠款资金水平的制造成本。为了支持可能的 从最初的移植指征扩展到母胎传播指征，我们提出了一个非 临床实验和监管战略计划在第三年的赠款。

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.