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依赖性的，抗体介导的治疗消融的有效反应 需要在宿主的细胞类型特异性FC受体和宿主和 治疗性单克隆抗体。许多患者缺乏有效反应，也许多达30％ 既代表机会又是描述这种差异的机械基础的挑战。 遗传查询可以确定宿主对这些差异的贡献。我们的初步数据 表明将近三分之一的人在经典FC基因座中具有结构性变异（SV） 流行的单核苷酸多态性影响配体结合的亲和力，受体迁移率 细胞膜和定量受体表达。这些较大的结构变体影响FC受体 在淋巴样和髓样细胞系列中，几乎三分之一的变体都没有表征 基因组结构，蛋白质结构的结果改变以及对净生物学功能的影响。新的， 创新的技术方法，包括链接阅读测序，现在已通过常规PCR确认 已经展示了基因组组织中的新结构。 CRISPR/CAS9的应用针对切除 该基因座，再加上链接阅读的测序，现在可以解决新的结构变化 影响生物学功能。再加上增强关键激活受体表达的潜力， 有一个极好的机会来增强宿主对治疗性mab的反应，但也可以 疫苗接种方案。因此，该提案的目的是1）我们的特征同类启用 具有不同祖先背景的捐助者（n> 5,000），以表征新颖的基因组组织 使用链接阅读，特定于基因座的切除和长阅读策略的结构变体； 2）确定 预测新型受体蛋白及其结构，并评估其表达和功能，包括 可能的诱饵，信号不足的结构； 3）开发一个可扩展的可概括平台来评估 人类FCGR遗传基因座中SNP的曲目和较大的基因组结构变异 我们不断扩大的供体池（> 10,000）中的人口多样性，并评估预测对反应的能力 治疗性抗体治疗。评估受体组合，其结构及其表达 将实现选择和分层的策略，以采用最佳的精确医学方法。