Valens-Poly Sequencing Polyclonal Antibodies for Drug Discovery

用于药物发现的 Valens-Poly 测序多克隆抗体

• 批准号: 9150642
• 负责人: Natalie Castellana
• 金额: $ 31.84万
• 依托单位: DIGITAL PROTEOMICS LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9150642
• 关键词: Address; Algorithms; Amino Acid Sequence; Animals; Antibodies; Antibody Repertoire; Antibody Response; Attention; B-Lymphocytes; Chemicals; Complement; Complex; DNA Sequence; Data; Data Set; Databases; Development; Disease; Drug resistance; Enzymes; Generations; Health; Human; Infection; Knowledge; Length; Maps; Mass Spectrum Analysis; Methods; Modification; Monoclonal Antibodies; Mutation; N-terminal; Peptide Sequence Determination; Peptides; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Process; Protein Isoforms; Proteins; Proteomics; Quality Control; RNA; Reporting; Sampling; Site; Small Business Innovation Research Grant; Specificity; Staging; Survivors; Technology; Therapeutic; Time; TimeLine; Transcript; Translating; Variant; base; cost; deamidation; digital; drug candidate; drug development; drug discovery; drug market; improved; next generation; next generation sequencing; novel therapeutics; oxidation; polyclonal antibody; screening; tandem mass spectrometry; tool

 DESCRIPTION (provided by applicant): Antibodies are ideal drug candidates due to high specificity for target molecules. Monoclonal antibodies represent one of the fastest growing segments of the drug market, however, recent attention has focused on polyclonal antibodies and monoclonal mixtures to reduce the opportunity for a disease to become drug resistant. Polyclonal antibodies sampled from disease survivors offer a wealth of new drug candidates. Direct proteomic sequencing of the circulating antibodies is the fastest method to determine the antibody response to a disease, and is a prerequisite for drug development. Previously, we created a mass spectrometry-based, monoclonal antibody sequencing tool, Valens, which we will extend in order to sequence complex antibody samples containing polyclonal antibodies or mixtures of monoclonal antibodies. Current technologies for developing drugs from circulating polyclonal antibodies require weeks of lab time, while our tool, Valens-Poly, will reduce that time to just days. Chemical modifications to the antibody, such as oxidation and deamidation, may impact the bioactivity and be the result of improper handling. Valens-Poly will identify sites of modification in order to improve quality control of drug candidates. Finally, we will create an interactive interface for Valens-Poly so that it may integrate expert human knowledge with the automated sequencing algorithms. Our tool will also utilize datasets that complement mass spectrometry when available, including Edman degradation-produced N-terminal sequences or next generation sequencing of transcripts.

 说明(申请人提供)：抗体是理想的候选药物，因为它对靶分子有很高的特异性。单抗是药物市场增长最快的领域之一，然而，最近的注意力集中在多克隆抗体和单克隆混合物上，以减少疾病产生抗药性的机会。从疾病幸存者身上采集的多克隆抗体提供了大量新的候选药物。直接对循环抗体进行蛋白质组学测序是确定抗体对疾病反应的最快方法，也是药物开发的先决条件。在此之前，我们创建了一个基于质谱学的单抗测序工具Valens，我们将对其进行扩展，以便对包含多克隆抗体或单抗混合物的复杂抗体样本进行排序。目前从循环多克隆抗体开发药物的技术需要数周的实验室时间，而我们的工具Valens-Poly将缩短这一时间 只有几天了。对抗体的化学修饰，如氧化和脱酰胺，可能会影响其生物活性，并可能是处理不当的结果。Valens-Poly将确定修饰位置，以改善候选药物的质量控制。最后，我们将为Valens-Poly创建一个交互界面，以便它可以将专家的人类知识与自动测序算法相结合。我们的工具还将利用补充质谱学的数据集，包括Edman降解产生的N-末端序列或下一代转录本测序。