PO.ET02.13 · 实验与分子治疗
通过AcroAIxTM推进蛋白质工程：以AI驱动的策略优化结构与功能
Advancing protein engineering through AcroAIxTM: AI-driven strategies for enhanced structure and function optimization
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作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
重组蛋白是生物制造中不可或缺的工具，为从生物制剂到细胞治疗等一系列药物开发和生产工艺提供支撑。细胞通路由多种信号通路的调控所驱动，这些通路由众多蛋白质和膜受体组成。然而，某些蛋白质在体外重现存在重大挑战，尤其是当其三级和四级结构复杂时。这导致所得蛋白稳定性有限、半衰期短、生物活性不一致，进而限制了可重复性、增加了生产成本，并对可扩展生产构成重大障碍。在许多情况下，传统的蛋白质工程策略虽然有价值，但受限于实验通量和有限的预测准确性。为克服这一挑战，AcroAIxTM应运而生，它是一个AI驱动的蛋白质设计平台，整合了结构建模、机器学习和序列-功能预测，以系统性地生成高性能的蛋白质变体。通过优化关键的生物物理参数，AcroAIxTM能够对重组蛋白进行理性改造，以提升其构象稳定性、功能性半衰期和结合效率。这些进展在细胞培养应用中尤为重要，其中白细胞介素-21（IL-21）和成纤维细胞生长因子2（FGF-basic）等生长因子必不可少。我们开发了热稳定形式的IL-21和FGF-basic，使其在37℃培养基中3天内保持生物活性和半衰期。与野生型相比，所得细胞因子在更长时间内保持活性，并在减少喂养的方案下显著提高细胞计数。因此，改造出具有增强稳定性和生物活性的变体，可直接提高培养的稳健性、减少因子补充需求，并提升基于细胞的生产工作流程的效率。通过将计算设计与实验验证相结合，AcroAIxTM平台为重组蛋白创新建立了一个变革性框架，推动了通用生物制造实践和细胞培养驱动的治疗性生产。
查看英文原文 English abstract
Recombinant proteins are indispensable tools in biomanufacturing, underpinning drug development and manufacturing processes ranging from biologics to cell therapies. Cellular pathways are driven by the modulation of varying signaling pathways comprising of numerous proteins and membrane receptors. However, reproducing certain proteins ex vivo poses a significant challenge, especially when the tertiary and quaternary structure are complex. This results in a protein that suffers from limited stability, short half-life, and inconsistent bioactivity which further restricts reproducibility, production costs, and poses a significant barrier to scalable manufacturing. In many cases, traditional protein engineering strategies, while valuable, are constrained by experimental throughput and limited predictive accuracy. To overcome this challenge, AcroAIxTM is an artificial intelligence-driven protein design platform that integrates structural modeling, machine learning, and sequence-function prediction to systematically generate high-performing protein variants. By optimizing key biophysical parameters, AcroAIxTM enables the rational enhancement of recombinant proteins for improved conformational stability, functional half-life, and binding efficiency. These advances are particularly impactful in cell culture applications, where growth factors such as interleukin-21 (IL-21) and fibroblast growth factor 2 (FGF-basic) are essential. Heat-stable forms of IL-21 and FGF-basic were developed to maintain their bioactivity and half-life in 37ºC media for 3 days. The resulting cytokine remains active for a longer period and improves cell counts significantly under a reduced-feeding protocol compared to wild types. As such, engineering variants with enhanced stability and bioactivity can directly improves culture robustness, reduce factor replenishment requirements, and increase the efficiency of cell-based manufacturing workflows. By bridging computational design with experimental validation, the AcroAIxTM platform establishes a transformative framework for recombinant protein innovation, advancing both general biomanufacturing practices and cell culture-driven therapeutic production.
利益披露 Disclosure
S. Chiang, None..
J. Liu, None..
L. Chou, None..
A. Ouyang, None..
L. Qin, None.