Therapeutic Antibodies for CMV

CMV 治疗抗体

基本信息

批准号：
8791595
负责人：
Lawrence Michael Kauvar
金额：
$ 99.09万
依托单位：
TRELLIS BIOSCIENCE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8791595
关键词：
Adverse effects Affinity Animal Model Antibodies Antibody Affinity Antibody-Producing Cells B-Lymphocytes Biochemical Blood CMV glycoprotein B Capsid Proteins Cardiovascular Diseases Cell Line Cells Cessation of life Chorionic villi Clinical Clinical Trials Congenital Abnormality Cytomegalovirus Cytomegalovirus Infections Development Disease Dose Endothelial Cells Epithelial Epithelial Cells Epitopes Fetal Growth Retardation Fibroblasts First Pregnancy Trimester Funding Geographic Locations Glycoproteins Goals Human Human Cloning Human Pathology Immunoglobulins Immunosuppression Implant In Vitro Incidence Infant Infection Infection prevention Infectious Agent Investments Lead Licensing Life Live Birth Liver Measures Medical Modeling Monoclonal Antibodies Morbidity - disease rate Nature Neurologic Organ Culture Techniques Organ Transplantation Outcome Passive Immunization Passive Immunotherapy Pathology Pharmacologic Substance Phase Placenta Placentation Plasma Population Positioning Attribute Pregnancy Pregnancy Complications Production Proteins Quality Control Readiness Recurrence Regimen Reporting Respiratory syncytial virus Retinal Diseases Risk Role SCID Mice SCID-hu Mice Safety San Francisco Site Specificity Technology Testing Text Therapeutic Therapeutic antibodies Thymus Gland Tissues Transplant Recipients Transplantation United States Vaccination Vaccines Villous Villus Viral Viral Antibodies Virulent Virus Virus Diseases Woman Work Xenograft procedure attributable mortality cell type commercialization cost deafness design drug candidate fetal fetal infection fetus cell human monoclonal antibodies human tissue improved in utero in vivo innovation interest liver xenograft medical complication meetings phase 2 study prenatal prevent protein B research clinical testing research study seropositive stillbirth transmission process

项目摘要

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.

描述（由申请人提供）：人类巨细胞病毒（HCMV）是导致出生缺陷和器官移植相关医疗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) 比 HIG 具有主要优势，包括安全性、功效、效力、生产效率和质量控制。通过使用其先进的单克隆抗体发现技术 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单克隆抗体。使用有毒临床菌株 VR1814 进行的体外中和研究表明，CMV345 的效力比任何先前描述的 gB mAb 强 5-10 倍，比 HIG 强数倍。它针对感染所有细胞类型所必需的菌株不变表位，为与人类病理相关的所有特殊细胞类型提供保护，包括成纤维细胞、上皮细胞、内皮细胞和原代胎盘滋养层细胞 (CTB)。格子与加州大学 Lenore Pereira 博士合作旧金山旨在确定 CMV345 对作为体外分离细胞的 CTB 以及作为离体组织外植体或作为异种移植物移植到 SCID-hu 小鼠体内的人胎盘模型的功效。这些开创性的模型为预期这种主要候选单克隆抗体在阻断胎盘感染、减少强毒菌株对胎盘发育的早期致病作用以及防止病毒在子宫胎盘界面传播方面的高效性提供了强有力的理由。因此，CMV345 是替代和改善 HIG 的被动免疫疗法的有希望的候选者。我们正在提交此快速通道申请，以便尽快使 CMV345 做好临床测试的准备。第一阶段概念验证实验完成后，重点是确认和扩展此处提出的初步结果，第二阶段研究将重点关注支持 IND 的制造，并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 模型优化剂量方案外，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者 HCMV 疾病模型的实用性。该项目的最终交付成果将是一种可用于 IND 的 HCMV 天然人类治疗性抗体，该抗体在预防广泛范围内的所有相关细胞类型感染方面非常有效 HCMV 毒株。