Therapeutic Antibodies for CMV

描述（由申请人提供）：人巨细胞病毒（HCMV）是出生缺陷和器官移植相关医学并发症的主要病毒原因。使用人免疫球蛋白（HIG）的被动免疫已被证明可以预防疾病。然而，作为混合血浆，HIG是一种可变产品，可能含有感染因子或可能引起副作用。从人血液中克隆的天然人单克隆抗体（mAb）提供了超过HIG的主要优势，包括安全性、有效性、效力、生产效率和质量控制。通过使用其先进的mAb发现技术CellSpot（tm），Trellis Bioscience发现了一种针对HCMV糖蛋白B（gB）的亚纳摩尔亲和力天然人mAb。用临床强毒株VR 1814进行的体外中和研究表明，CMV 345的效力比任何先前描述的gB mAb强5-10倍，比HIG强几倍。它靶向所有细胞类型感染所必需的菌株不变表位，为与人类病理学相关的所有特化细胞类型提供保护，包括成纤维细胞、上皮细胞、内皮细胞和原代胎盘细胞滋养层细胞（CTB）。网格 与加州大学的莲娜佩雷拉博士合作San弗朗西斯科，以确定CMV 345对CTB的功效，CTB作为体外分离的细胞，在人胎盘模型中作为离体组织外植体或作为异种移植物移植到SCID-hu小鼠体内。这些开创性模型为预期该先导候选mAb在阻断胎盘感染、降低强毒株对胎盘发育的早期致病作用以及预防子宫-胎盘界面的病毒传播方面的高疗效提供了有力的依据。因此，CMV 345是用于被动免疫疗法以替代和改善HIG的有希望的候选物。我们提交这份快速通道申请是为了尽快使CMV 345准备好进行临床试验。在I期概念验证实验完成后，重点是确认和扩展本文提出的初步结果，II期研究将重点关注IND使能生产和进一步阐明设计临床策略所需的作用机制。除了使用胎儿-母体胎盘相互作用的SCID-hu模型优化给药方案外，我们还将探索在SCID小鼠中使用人胸腺/肝脏植入物的移植受体中HCMV疾病模型的实用性。该项目的最终交付成果将是一种IND就绪的HCMV天然人治疗抗体，该抗体在预防所有相关细胞类型的感染方面非常有效， HCMV毒株。

DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) is the major viral cause of birth defects and of medical complications associated with organ transplantation. Passive immunization using human immune globulin (HIG) has been shown to prevent disease. As pooled plasma, however, HIG is a variable product that potentially contains infectious agents or may cause side effects. Native human monoclonal antibodies (mAbs), cloned from human blood, offer major advantages over HIG including safety, efficacy, potency, production efficiency and quality control. By using its advanced mAb discovery technology, CellSpot(tm), Trellis Bioscience has discovered a sub-nanomolar affinity native human mAb against HCMV glycoprotein B (gB). Neutralization studies in vitro with a virulent clinical strain, VR1814, showe that CMV345 is 5-10 fold more potent than any previously described gB mAb and several-fold more potent than HIG. It targets a strain-invariant epitope essential for infection of all cell typs, providing protection for all of the specialized cell types relevant to the human pathology including fibroblast, epithelial, endothelial and primary placental cytotropoblasts (CTBs). Trellis has collaborated with Dr. Lenore Pereira at U.C. San Francisco to establish the efficacy of CMV345 on CTBs as isolated cells in vitro and in models of the human placenta as tissue explants ex vivo or transplanted as xenografts in SCID-hu mice in vivo. These pioneering models provide a strong rationale for expecting high efficacy of this lead candidate mAb for blocking infection of the placenta, reducing the early pathogenic effects of virulent strains on placental development, and preventing virus transmission at the uterine-placental interface. Thus, CMV345 is a promising candidate for passive immune therapy to replace and improve upon HIG. We are submitting this Fast-Track application to bring CMV345 to readiness for clinical testing as expeditiously as possible. After the Phase I proof of concept experiments are completed, focused on confirming and extending the preliminary results presented here, Phase II studies will focus on IND-enabling manufacturing and on further elucidation of the mechanism of action needed to design the clinical strategy. In addition to optimizing the dose regimen using the SCID-hu model of fetal-maternal placenta interaction, we will explore utility in a model for HCMV disease in transplant recipients using human thymus/liver implants in SCID mice. The final deliverable from this project will be an IND-ready native human therapeutic antibody to HCMV, which is highly effective at preventing infection of all relevant cell types by a broad range of HCMV strains.