Host Factors in Response to Therapeutic Monoclonal Antibodies and Vaccination

对治疗性单克隆抗体和疫苗接种的宿主因素

• 批准号: 10089400
• 负责人: Robert P. Kimberly
• 金额: $ 44.52万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10089400
• 关键词: Ablation; Affect; Affinity; African; Antibodies; Antibody Therapy; Biological; Biological Process; CRISPR/Cas technology; Cell membrane; Cells; Clinical; Clinical Investigator; Consensus; Coupled; Data; Effectiveness; European; Excision; FCGR2C gene; FCGR3A gene; Fc Receptor; Genes; Genetic; Genomics; Human; Immune response; Individual; Integration Host Factors; Laboratories; Ligand Binding; Link; Lymphoid Cell; Mediating; Modeling; Monoclonal Antibody Therapy; Myeloid Cells; Patients; Persons; Phagocytosis; Population Heterogeneity; Proteins; Protocols documentation; Reagent; Resolution; SNP genotyping; Series; Signal Transduction; Single Nucleotide Polymorphism; Stratification; Structure; Terminator Codon; Therapeutic; Therapeutic Monoclonal Antibodies; Therapeutic antibodies; Vaccination; Variant; antibody engineering; antibody-dependent cell cytotoxicity; cell type; cohort; cytokine; genetic variant; genomic locus; innovation; macrophage; monocyte; nanopore; novel; precision medicine; predicting response; premature; protein structure; receptor; receptor expression; response; structural genomics; translational scientist

PROJECT SUMMARY. Effective responses in Fc-dependent, antibody-mediated killing for therapeutic ablation require efficient and productive interactions between the cell-type specific Fc receptors of the host and the therapeutic monoclonal antibody. The lack of effective responses in many patients, perhaps as much as 30%, represents both an opportunity and a challenge to delineate the mechanistic basis for such differences. Genetic inquiry can identify the contributions that the host brings to these differences. Our preliminary data indicate that nearly one-third of persons have structural variants (SV) in the classical Fc locus in addition to the prevalent single nucleotide polymorphisms affecting affinity of ligand binding, receptor mobility in the plane of the cell membrane and quantitative receptor expression. These larger structural variants affect Fc receptors on both lymphoid and myeloid cell series, and nearly a third of these variants are uncharacterized in terms of genomic structure, resultant alterations in protein structure and impact on net biological function. New, innovative technical approaches including linked-reads sequencing, now confirmed with conventional PCR, have demonstrated novel structures in genomic organization. Application of CRISPR/Cas9 targeted excision of the locus, coupled with linked-reads sequencing now enables resolution of novel structural variations impacting biological function. Coupled with the potential to enhance expression of key activating receptors, there is the exceptional opportunity to enhance both the host response to therapeutic mAbs but also to vaccination protocols. Accordingly, the aims of this proposal are 1) enabled by our characterized cohort of donors (N > 5,000) with different ancestral backgrounds, to characterize the genomic organization of novel structural variants using linked-read, locus specific excision and long read strategies; 2) to identify the predicted novel receptor proteins and their structures and assess their expression and function, including possible decoy, signaling deficient structures; and 3) to develop a scalable, generalizable platform to assess the repertoire of SNPs and larger genomic structural variants in the human FCGR genetic locus to understand the population diversity in our expanding donor pool (>10,000) and assess the ability to predict response to therapeutic antibody therapy. Assessment of the portfolio of receptors, their structures and their expression will enable strategies for selection and stratification of recipients for an optimal precision medicine approach.

项目摘要。 Fc 依赖性抗体介导杀伤的有效反应以实现治疗性消融 需要宿主和细胞的细胞类型特异性 Fc 受体之间有效且富有成效的相互作用 治疗性单克隆抗体。许多患者（可能高达 30%）缺乏有效的反应， 描述这种差异的机制基础既是机遇也是挑战。 遗传探究可以确定宿主对这些差异的贡献。我们的初步数据 表明近三分之一的人除了 Fc 基因座外还存在结构变异 (SV) 普遍的单核苷酸多态性影响配体结合的亲和力，受体在平面上的迁移率 细胞膜和定量受体表达。这些较大的结构变异影响 Fc 受体 在淋巴和骨髓细胞系列上，其中近三分之一的变体在以下方面没有特征 基因组结构、蛋白质结构的变化以及对净生物功能的影响。新的， 创新的技术方法，包括链接读取测序，现已通过常规 PCR 得到证实， 已经证明了基因组组织的新颖结构。 CRISPR/Cas9靶向切除的应用 该位点的序列与链接读取测序相结合现在可以解决新的结构变异 影响生物功能。再加上增强关键激活受体表达的潜力， 这是一个绝佳的机会，既可以增强宿主对治疗性单克隆抗体的反应，也可以增强宿主对单克隆抗体的反应。 疫苗接种方案。因此，该提案的目标是 1）由我们的特征群体实现 具有不同祖先背景的捐赠者（N > 5,000），以表征新颖的基因组组织 使用链接读、位点特异性切除和长读策略的结构变体； 2) 识别 预测新的受体蛋白及其结构并评估其表达和功能，包括 可能的诱饵、信号缺陷结构； 3) 开发一个可扩展、通用的平台来评估 人类 FCGR 基因座中的 SNP 和更大的基因组结构变异的全部内容，以了解 我们不断扩大的捐助者库中的人口多样性（> 10,000）并评估预测反应的能力 治疗性抗体疗法。评估受体组合、其结构及其表达 将启用对接受者进行选择和分层的策略，以实现最佳的精准医疗方法。