Guo Yibo, Chen Xi, Fang Guchen, Cao Xuejun, Wan Junfen
State Key Laboratory of Bioreactor Engineering, Department of Bioengineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
Pharmaceutics. 2025 Apr 19;17(4):534. doi: 10.3390/pharmaceutics17040534.
Protein aggregation, particularly the aggregation of antibody-based drugs, has long been a significant challenge in downstream processes and formulation. While the inhibitory effects of excipients on aggregation have been extensively studied using early experimental characterization methods, complete formulation research requires significant amounts of antibodies and time, resulting in high research costs. This study proposed a quick and small-scale position-restrained simulation method which elucidated the mechanism of the reversible self-association (RSA) of antibodies and the influence of excipients on RSA under different conditions. We also validated the rationality of rapid and small-scale simulations through long-term (>1 μs) and large-scale (>1,000,000 atoms) simulations. : Through combing with simple stability characterization, the effects of different excipients on monomer residual content and the trend shown with concentration changes after thermal incubation were found to be similar to those observed in the simulations. Additionally, the formulation proposed by the simulations was validated using experimental characterization. : Simulations and experiments revealed the mechanism and showed consistent trends, providing better understanding for aggregation research.
蛋白质聚集，尤其是基于抗体的药物聚集，长期以来一直是下游工艺和制剂中的重大挑战。虽然使用早期实验表征方法对辅料对聚集的抑制作用进行了广泛研究，但完整的制剂研究需要大量抗体和时间，导致研究成本高昂。本研究提出了一种快速且小规模的位置受限模拟方法，该方法阐明了抗体可逆自聚集（RSA）的机制以及不同条件下辅料对RSA的影响。我们还通过长期（>1 μs）和大规模（>1,000,000个原子）模拟验证了快速和小规模模拟的合理性。通过与简单的稳定性表征相结合，发现不同辅料对单体残留含量的影响以及热孵育后随浓度变化呈现的趋势与模拟中观察到的相似。此外，模拟提出的制剂通过实验表征进行了验证。模拟和实验揭示了机制并呈现出一致的趋势，为聚集研究提供了更好的理解。
