抗体成药性筛选流程及评价策略

Antibody druggability screening process and evaluation strategy

摘要:

自1986年OKT3作为第一个治疗性单克隆抗体获批上市后，抗体技术及抗体药物迅猛发展。单克隆抗体、抗体片段、双(多)特异性抗体、融合蛋白、纳米抗体以及抗体偶联药物(antibody-drug conjugates, ADCs)等推陈出新，在肿瘤、血液、免疫、呼吸和代谢等相关疾病的治疗领域发挥着举足轻重的作用。抗体药物的发现过程，是通过多轮生物学功能评估和可成药性评估，筛选出具有安全、有效、稳定和可工艺放大的最佳候选序列，从而提高药物开发和临床研究的效率及成功率。抗体药物发现阶段的“成药性筛选与评估”已日益受到关注和重视，从药物发现和设计、先导分子筛选到候选分子确认，可及时发现分子潜在的物理化学风险因素，并评估可控性，保证后续药物开发过程中的质量稳定性。本文对抗体发现阶段的成药性筛选评估流程进行了分类和定义，涉及单克隆抗体、双特异性抗体、纳米抗体和ADCs等相关技术和药物形式，同时总结了成药性筛选评估中应重点关注的质量属性和高通量检测技术；系统性地阐述成药性开发流程和策略，为不断涌现的创新型药物的成药性筛选评估提供参考，大幅提高抗体药物开发的效率和成功率。

Abstract:

Since the approval of OKT3 as the first therapeutic monoclonal antibody in 1986, there has been rapid development in antibody technology and antibody drugs. Monoclonal antibodies, antibody fragments, bi (multi) specific antibodies, fusion proteins, nanobodies, and antibody-drug conjugates (ADCs) have been introduced and play a significant role in the treatment of oncology, hematology, immunology, respiratory, metabolic and other related diseases. The process of antibody drug discovery involves multiple rounds of biological function and druggability assessments to identify the best candidate sequences that are safe, effective, stable, and scalable. This lays the foundation for the efficiency and success of drug development and clinical studies. In the phase of antibody drug discovery, “druggability screening and evaluation” has received increasing attention. It involves drug discovery and design, screening and optimization of lead molecules as well as the validation of candidate molecules, with the aim of detecting potential physicochemical risk factors and evaluating controllability to ensure the quality stability of the subsequent drug development process. This paper classifies and defines the process of druggability screening and evaluation in the antibody discovery phase, covering monoclonal antibodies, bispecific antibodies, nanobodies, ADCs and other related technologies and drug forms. It also summarizes the quality attributes and high-throughput detection technology that should be emphasized in the druggability screening and evaluation. The systematic elaboration of the druggability development process and strategy provides a reference for the druggability screening and evaluation of emerging innovative drugs, significantly improving the efficiency and success rate of antibody drug development.