Assessment of self-association of monoclonal antibody molecules by analysis of the protein layer detected at the proximity of a solid surface

通过分析在固体表面附近检测到的蛋白质层来评估单克隆抗体分子的自缔合

• 批准号: 10726173
• 负责人: Reza Nejadnik
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10726173
• 关键词: Acceleration; Address; Adsorption; Area; Asthma; Atopic Dermatitis; Behavior; Biological Products; Buffers; Characteristics; Data; Development; Diffusion; Disease; Drug Formulations; Early identification; Equilibrium; Excipients; Excision; Exclusion; Failure; Formulation; Goals; Ionic Strengths; Measurement; Measures; Medical; Methods; Modeling; Monoclonal Antibodies; Multiple Sclerosis; Outcome; Patients; Pharmaceutical Preparations; Phase; Predisposition; Process; Property; Protein Analysis; Proteins; Quartz; Rationalization; Research; Resources; Rheumatoid Arthritis; Safety; Self Assessment; Solid; Specific qualifier value; Surface; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Viscosity; candidate identification; cost; drug candidate; drug development; drug discovery; improved; improved outcome; manufacturability; manufacturing process; novel; prevent; public health relevance; research and development; small molecule therapeutics; success; therapeutic development; therapeutic protein; tool

Despite the increasing availability of monoclonal antibody (mAb) drugs and their proven success in treatment of rheumatoid arthritis, multiple sclerosis, asthma, atopic dermatitis, and many other diseases, the early identification of the protein candidate molecules with desirable manufacturability, stability and delivery attributes remains a big challenge. Self-association and poor solution behavior, manifested in high viscosity/opalescence at relevant concentrations or in phase separation and stability issues, are major limiting factors in development of mAb therapeutics. Solution behavior is believed to be governed by protein self-association, however, measurement of these associations experimentally and prediction of the solution behavior are challenging using the current methods. The objective in this application is to develop a versatile method that directly measures the protein self-association under relevant conditions and is predictive of the important attributes in drug development and formulation. This proposal is significant because it increases the potential to identify the candidates with weak solution behavior and susceptibility to aggregation which, in turn, can lead to enhanced efficiency in development of much needed mAb therapeutics. In addition, having reliable predictive methods at the early stages of drug discovery and development would eliminate the early, unwarranted removal of therapeutically promising mAb drug candidates from development pipelines.

尽管单克隆抗体 (mAb) 药物的可用性不断增加，并且在治疗类风湿性关节炎、多发性硬化症、哮喘、特应性皮炎和许多其他疾病方面取得了成功，但仍需尽早鉴定出具有理想的可制造性、稳定性和递送属性的蛋白质候选分子。仍然是一个巨大的挑战。自缔合和不良溶液行为（表现为相关浓度下的高粘度/乳光或相分离和稳定性问题）是 mAb 疗法开发的主要限制因素。溶液行为被认为是由蛋白质自缔合控制的，然而，使用当前的方法对这些缔合进行实验测量和预测溶液行为具有挑战性。本申请的目标是开发一种通用方法，可以直接测量相关条件下的蛋白质自缔合，并预测药物开发和配方中的重要属性。该提议意义重大，因为它增加了识别具有弱溶液行为和对聚集敏感的候选者的潜力，这反过来又可以提高急需的单克隆抗体疗法的开发效率。此外，在药物发现和开发的早期阶段拥有可靠的预测方法将消除从开发管道中过早、无根据地移除有治疗前景的 mAb 候选药物的情况。