Pharmacokinetics of Natural and Engineered Secreted Factors Delivered by Mesenchymal Stromal Cells

Transient cell therapy is an emerging drug class that requires new approaches for pharmacological monitoring during use. Human mesenchymal stem cells (MSCs) are a clinically-tested transient cell therapeutic that naturally secrete anti-inflammatory factors to attenuate immune-mediated diseases. MSCs were used as a proof-of-concept with the hypothesis that measuring the release of secreted factors after cell transplantation, rather than the biodistribution of the cells alone, would be an alternative monitoring tool to understand the exposure of a subject to MSCs. By comparing cellular engraftment and the associated serum concentration of secreted factors released from the graft, we observed clear differences between the pharmacokinetics of MSCs and their secreted factors. Exploration of the effects of natural or engineered secreted proteins, active cellular secretion pathways, and clearance mechanisms revealed novel aspects that affect the systemic exposure of the host to secreted factors from a cellular therapeutic. We assert that a combined consideration of cell delivery strategies and molecular pharmacokinetics can provide a more predictive model for outcomes of MSC transplantation and potentially other transient cell therapeutics.

瞬时细胞疗法是一类新兴的药物品类，其临床应用过程中亟需全新的药理学监测方案。人源间充质干细胞（human mesenchymal stem cells, MSCs）是一款经过临床验证的瞬时细胞治疗制剂，可天然分泌抗炎因子以缓解免疫介导性疾病。本研究以MSCs作为概念验证模型，提出核心假说：相较于仅检测细胞的生物分布，测量细胞移植后分泌因子的释放水平，可作为替代监测手段，用以评估受试对象对MSCs的暴露情况。通过比较细胞定植情况与移植物分泌的相关血清因子浓度，本研究观察到MSCs与其分泌因子的药代动力学特征存在显著差异。对天然或工程化分泌蛋白、活性细胞分泌通路以及清除机制的影响展开探索后，本研究揭示了影响宿主对细胞治疗制剂分泌因子的全身暴露水平的全新维度。本研究认为，综合考量细胞递送策略与分子药代动力学特征，可为MSCs移植乃至其他瞬时细胞疗法的预后转归提供更具预测性的分析模型。