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（申请人提供）：新生儿Fc受体（FcRn）有四个主要功能：IgG和白蛋白的分解代谢保护、IgG的转胞吞作用和抗原呈递。 FcRn 在许多组织中发挥作用，对于新生儿通过初乳和乳汁获取母体 IgG、IgG 的肺部分泌以及 IgG 和免疫复合物跨成人肠上皮的双向转运至关重要。它还参与 T 细胞抗原呈递。 IgG 在临床上取得的重大成功是作为“灵丹妙药”精确靶向和治疗多种人类疾病，特别是癌症和炎症性疾病。这一成功部分归因于与其他血清蛋白相比，它们的体内半衰期较长。与我们的了解了 FcRn 在此过程中的关键作用后，解决血清蛋白和小分子半衰期的新治疗领域已经出现。这个新领域的主要参与者是 IgG Fc 结构域和白蛋白：临床相关分子通过融合附着在这些分子上，延长了它们的功能性体内半衰期。化合物的功能性半衰期延长具有许多临床益处，包括：（i）减少有效剂量（减少不良反应）； (ii) 减少给药频率（延长药代动力学）； (iii) 提高生物利用度； (iv) 降低生产成本。 IgG 和融合化合物的治疗开发的关键是临床前模型，它准确地反映了人体生理学。然而，FcRn 在人类和啮齿动物之间表现出物种歧视结合差异。为了克服这个问题，开发了缺乏小鼠 FcRn 并表达人 FcRn (hPcRn) 的小鼠。尽管有用，但这些模型表达小鼠 IgG，而 hFcRn 和小鼠白蛋白不能有效保护它们。这并不反映正常的生理情况。对于白蛋白，目前还没有容易获得的模型。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IgG2b的Fc结构域与人Fc交换，并用人白蛋白替换小鼠白蛋白基因。为此，我们将使用 TAL 效应核酸酶在感兴趣区域的侧翼引入异特异性重组酶靶位点，然后通过重组介导的盒交换来直接对现有人源化 FcRn 小鼠模型的受精卵进行基因改造。通过对当前模型进行连续修改来创建这些新菌株，我们将基于它们之前的使用和声誉（数据），加快其实施速度。经过验证后，这些新菌株将通过 JAX 小鼠存储库进行分发。我们完全期望这些模型能够更准确地反映人 IgG 和人白蛋白生物学，从而快速推进药物开发和 FcRn 生物学。