Humanization of hFcRn Mice for Physiological Evaluation of Therapeutic Antibodies

hFcRn 小鼠人源化用于治疗性抗体的生理学评价

基本信息

批准号：
8476421
负责人：
Michael Van Wiles
金额：
$ 16.87万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-13 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8476421
关键词：
Address Adult Advanced Development Adverse reactions Affinity Albumins Animal Model Antibodies Antigen Presentation Antigen-Antibody Complex Autoimmune Process Binding Biological Assay Biological Availability Biology Chimeric Proteins Clinical Clinical Trials Colostrum Communities Data Development Diabetes Mellitus Discrimination Disease Drug Kinetics Engineering Epithelial Cells Evaluation Exhibits Fc domain Frequencies Gene Deletion Gene Transfer Techniques Genes Genetic Engineering Genetic Recombination Goals Half-Life Human Immunoglobulin G Immunoglobulin Variable Region Inflammatory Knockout Mice Left Life Extension Lung Magic Malignant Neoplasms Mediating Methods Methotrexate Milk Modeling Modification Monoclonal Antibodies Mus National Institute of Allergy and Infectious Disease National Institute of Diabetes and Digestive and Kidney Diseases Neonatal Physiological Physiological Processes Physiology Pre-Clinical Model Process Production Proteins Public Health Rodent Role Sales Serum Serum Albumin Serum Proteins Site Speed Study models System T-Lymphocyte Technology Therapeutic Therapeutic Monoclonal Antibodies Therapeutic antibodies Tissues Work base cancer therapy chimeric gene clinically relevant cost dosage drug development embryonic stem cell glucagon-like peptide 1 human monoclonal antibodies improved in vivo interest intestinal epithelium man mouse model neonatal Fc receptor novel novel therapeutics nuclease pre-clinical pre-clinical research preclinical study public health relevance recombinase repository small molecule success therapeutic development therapeutic protein transcytosis zygote

项目摘要

DESCRIPTION (provided by applicant): The neonatal Fc receptor (FcRn) has four major functions: catabolic protection of IgG and albumin, transcytosis of IgG and antigen presentation. FcRn functions across many tissues and is critical for neonatal acquisition of maternal IgG via colostrum and milk, the pulmonary secretion of IgG and bidirectional transport of both IgG and immune complexes across the adult intestinal epithelium. It is also involved in T cell antigen presentation. A major clinical success of IgGs is as a "magic bullet" precisely targeting and treating a wide array of human disorders, especially cancer and inflammatory diseases. This success is due, in part, to their long half-life in vivo compared to other serum proteins. With our understanding of the critical role of FcRn in this process, a new therapeutic field addressing serum proteins and small molecules half-life has emerged. The major players of this new field are the IgG Fc domain and albumin: clinically relevant molecules are attached to these via fusion extending their functional in vivo half- life. Functional half-life extension of compounds has a number of clinical benefits including: (i) reduction of effective dosage (reducing adverse reactions); (ii) reduced frequency of administration (extended pharmacokinetics); (iii) improved bioavailability; and (iv) a reduction of production costs. Critical for therapeutic development of IgGs and fusion compounds are preclinical models, which accurately reflect human physiology. However, FcRn exhibits species-discrimination binding differences between human and rodents. To overcome this, mice lacking the mouse FcRn and expressing human FcRn (hPcRn) were developed. Although useful, these models express mouse IgGs, which are not effectively protected by hFcRn and mouse albumin. This does not reflect the normal physiological situation. For albumin there is currently no model easily available. To establish models that better reflect the human physiological processes, we propose to exchange the Fc domain of mouse lgG2b with human Fc and to replace the mouse albumin gene with human albumin. To do this, we will use TAL effector nucleases to introduce heterospecific recombinase target sites flanking the region of interest, followed by recombination mediated cassette exchange to directly genetically engineer the zygote of existing humanized FcRn mouse models. By creating these new strains via sequential modification of current models we will build upon their previous use and reputation (data), speeding their implementation. After verification, these novel strains will be distributed via the JAX Mouse Repository. We fully expect these models to more accurately reflect human IgG and human albumin biology and, therefore, rapidly advance drug development and FcRn biology.

描述（由申请人提供）：新生儿FC受体（FCRN）具有四个主要功能：IgG和白蛋白的分解代谢保护，IgG的跨胞菌病和抗原表现。 FCRN在许多组织中起作用，对于通过初乳和牛奶，IgG的肺部分泌以及在成年肠上皮的成年肠上皮跨IgG和免疫复合物的双向转运的孕产妇IgG和双向转运至关重要。它也参与T细胞抗原表现。 IgGS的主要临床成功是“魔术子弹”，正是针对和治疗各种各样的人类疾病，尤其是癌症和炎症性疾病的“魔术子弹”。与其他血清蛋白相比，这一成功部分归因于它们长期寿命。与我们的了解FCRN在此过程中的关键作用，已经出现了一种新的治疗领域，以解决血清蛋白和小分子半衰期。这个新领域的主要参与者是IgG FC域和白蛋白：临床相关的分子是通过融合延长其在体内半生活中的功能性的。化合物的功能性半衰期扩展具有许多临床益处，包括：（i）减少有效剂量（减少不良反应）；（ii）降低给药频率（扩展药代动力学）；（iii）改善生物利用度；（iv）降低生产成本。对于IgG和融合化合物的治疗开发至关重要的是临床前模型，它准确地反映了人类的生理学。但是，FCRN表现出人与啮齿动物之间的种类歧视结合差异。为了克服这一点，开发了缺乏小鼠FCRN和表达人FCRN（HPCRN）的小鼠。尽管有用，但这些模型表达了小鼠IgG，这些IgGS并非受HFCRN和小鼠白蛋白有效保护。这不能反映正常的生理状况。对于白蛋白，目前尚无容易获得的模型。为了建立更好地反映人类生理过程的模型，我们建议将小鼠LGG2B的FC结构域与人FC交换，并用人白蛋白代替小鼠白蛋白基因。为此，我们将使用TAL效应子核酸酶引入感兴趣区域的杂种重组酶靶位点，然后进行重组介导的盒式交换，直接在基因上设计现有的人源化FCRN小鼠模型的合子。通过对当前模型的顺序修改创建这些新菌株，我们将基于其先前的使用和声誉（数据），从而加快其实现。验证后，这些新型菌株将通过JAX小鼠存储库分布。我们完全期望这些模型能够更准确地反映人类IgG和人白蛋白生物学，因此可以迅速提高药物开发和FCRN生物学。