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: 7487309
• 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/7487309
• 关键词: Accounting; Affinity; Algorithms; Anthrax disease; Antibodies; Antidotes; Antigen-Antibody Complex; Antigens; Antineoplastic Agents; Arthritis; Binding; Biological; Biological Models; Class; 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; Personal Satisfaction; Pharmaceutical Preparations; Phase; Placement; Postdoctoral Fellow; Process; Protein Analysis; Protein Engineering; Proteins; Public Health; Research; Research Personnel; Resolution; Sampling; Score; Side; Specificity; Structure; System; Techniques; Technology; Testing; Therapeutic antibodies; Thermodynamics; Time; Uncertainty; Vertebral column; anthrax toxin; base; blind; computerized tools; cytotoxic; design; drug mechanism; 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)：治疗性抗体是目前正在开发的药物的主要类别，因为它们可以与体内或感染剂上的特定目标结合，具有高亲和力和特异性。与其抗原结合的治疗性抗体的结构可能有助于揭示药物作用机制的结构起源，并可能表明抗原本身在疾病过程中的机制。此外，该结构还可用于进一步的蛋白质工程，如增加结合亲和力。我们建议开发工具来预测抗体-抗原复合体的结构，从抗体的序列和抗原的未结合结构开始。我们将改进和定制对接评分函数，开发用于对接的同源模型，并开发用于对接的灵活循环算法，以解决同源抗体结构中的不确定性。抗体是同源对接和灵活环对接的理想测试系统，因为免疫球蛋白折叠是明确定义的；当这些技术被开发出来时，它们将对对接领域产生广泛的影响。最后，我们将把这些技术应用于抗体-抗原复合体结构未知的两个模型系统。单抗806与表皮生长因子受体结合，已被证明是治疗几种类型肿瘤的有效方法。14B7抗体家族结合炭疽毒素，防止其细胞毒性作用。这两种复杂结构目前都是未知的。我们将预测结构，并合作通过实验来验证预测。这项研究与公众健康相关，因为它将为发现新的蛋白质药物的结构机制提供通用的计算工具。此外，这项研究还将确定与其靶点结合的新型抗癌药物和与炭疽毒素结合的新型解毒剂的结构，揭示这些治疗方法的结构基础，并为定制药物以提高其有效性提供基础。