Prediction of the Structure of Therapeutic Antibodies with their Antigens

治疗性抗体结构及其抗原的预测

• 批准号: 7680247
• 负责人: JEFFREY J GRAY
• 金额: $ 26.65万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7680247
• 关键词: Accounting; Affinity; Algorithms; Anthrax disease; Antibodies; Antidotes; Antigen-Antibody Complex; Antigens; Antineoplastic Agents; Arthritis; Binding; Biological; Biological Models; Complex; Crystallography; Development; Discrimination; Disease; Docking; Drug effect disorder; Effectiveness; Epidermal Growth Factor Receptor; Family; Fellowship; Foundations; Gray unit of radiation dose; HIV Infections; Homology Modeling; Immunoglobulin G; Infectious Agent; International; Malignant Neoplasms; Methods; Modeling; Modification; Molecular Conformation; Monoclonal Antibodies; Multiple Sclerosis; Mutagenesis; Pharmaceutical Preparations; Phase; Postdoctoral Fellow; Process; Protein Analysis; Protein Engineering; Proteins; Public Health; Research; Research Personnel; Resolution; Sampling; Side; Specificity; Structure; System; Techniques; Technology; Testing; Therapeutic antibodies; Thermodynamics; Time; Uncertainty; Vertebral column; anthrax toxin; base; blind; computerized tools; cytotoxic; design; drug mechanism; effective therapy; flexibility; human disease; improved; improved functioning; interest; monomer; novel; novel therapeutics; prevent; programs; protein folding; protonation; tool; tumor

DESCRIPTION (provided by applicant): Therapeutic antibodies constitute a major class of current drugs under development because they can bind with high affinity and specificity to particular targets in the body or on an infectious agent. The structure of a therapeutic antibody bound to its antigen can be of value to reveal the structural origin of the mechanism of the drug's action and possibly indications of the mechanism of the antigen itself in a disease process. Also, the structure can be exploited for further protein engineering such as increasing binding affinity. We propose to develop tools to predict the structure of antibody-antigen complexes starting from the sequence of the antibody and an unbound structure of the antigen. We will improve and tailor docking scoring functions, develop homology models for docking, and develop flexible loop algorithms for docking to account for uncertainties in a homology antibody structure. Antibodies make an ideal test system for homology docking and flexible loop docking because the IgG fold is well-defined; when these techniques are developed, they will be of broad impact for the docking field in general. Finally, we will apply these techniques to two model systems for which the antibody-antigen complex structure is unknown. Monoclonal antibody 806 binds to the epidermal growth factor receptor and has been shown to be an effective therapy against several types of tumors. The 14B7 family of antibodies binds the anthrax toxin and prevents its cytotoxic effects. Both complex structures are currently unknown. We will predict structures and collaborate to validate the predictions experimentally. This research is relevant to public health because it will provide general computational tools to discover the structural mechanism of new protein drugs. In addition, this research will determine the structure for a novel cancer drug bound to its target and a novel antidote bound to the anthrax toxin, revealing the structural basis of the therapies and providing a foundation to tailor the drugs to increase their effectiveness.

描述（由申请人提供）：治疗性抗体构成了正在开发的当前药物的主要类别，因为它们可以与体内的特定靶标或感染剂具有高亲和力和特异性结合。与其抗原结合的治疗抗体的结构可以揭示该药物作用机理的结构起源，并可能在疾病过程中表明抗原本身的机制。同样，可以利用结构用于进一步的蛋白质工程，例如增加结合亲和力。我们建议开发工具，以预测从抗体的序列和抗原的未结合结构开始的抗体 - 抗原络合物的结构。我们将改善和量身定制对接得分功能，开发对接的同源模型，并开发灵活的循环算法，用于对接以说明同源抗体结构中的不确定性。抗体是同源对接和柔性循环对接的理想测试系统，因为IgG折叠的定义明确。当开发这些技术时，它们对总体上的对接领域会产生广泛的影响。最后，我们将将这些技术应用于两个模型系统，抗体 - 抗原复合物结构未知。单克隆抗体806与表皮生长因子受体结合，已被证明是对几种类型肿瘤的有效疗法。 14B7抗体家族结合炭疽毒素并防止其细胞毒性作用。目前，这两个复杂的结构都是未知的。我们将预测结构并协作以实验验证预测。这项研究与公共卫生有关，因为它将提供一般的计算工具来发现新蛋白质药物的结构机制。此外，这项研究将确定与其靶标结合的新型癌症药物的结构，并确定与炭疽毒素结合的新型解毒剂，揭示了疗法的结构基础，并提供了一个基础来调整药物以提高其有效性。