HCMV Therapeutic Antibody Safety Trial

摘要 人巨细胞病毒(HCMV)从母亲传播到胎儿与约15%的死产和 在美国，每年约有1.6万名出生缺陷。人巨细胞病毒也是引起相关医疗并发症的主要病毒原因。 骨髓和器官移植。抗人巨细胞病毒增强型人免疫被动免疫 球蛋白(HIG)对这两种适应症都显示出良好的活性。HIG是一种复杂、可变的产品，可能 引起非靶标抗体结合的副作用。单抗(MAb)具有质量优势 包括效力、安全、生产效率和质量控制在内的HIG。格子生物科学发现 抗人巨细胞病毒病毒粒子最保守位点(GB AD-2位点)的高亲和力天然人源单抗(TRL345) i)。TRL345是从人B组克隆的人IgG1kappa(G1m1，17(z，a)；KM3同种异型)单抗。 淋巴细胞。该单抗中和了所有四个主要血清型的15个临床分离株中的15个。它保护了所有 与人类病理学相关的特殊细胞类型。它在人体胎盘模型中也有完全的保护作用。 作为体外组织外植体生长的碎片。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。 已经开发出在CHO细胞中以商业有用的水平表达TRL345的主细胞库 (1.74g/L)，按250L GMP标准。所有支持IND的分析工作都已完成，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，第一批临床产品已经生产出来 有足够的材料进行1期和2期人体临床试验。我们建议在此进行第一阶段单次 健康志愿者递增剂量临床试验。

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.