化学小分子药物基于“蛋白酶体糜蛋白酶样活性-FcRn”通路影响单克隆抗体药物消除的作用机制及定量关系研究

联用甲氨蝶呤或雷公藤甲素等化学小分子药物可以显著降低单克隆抗体药物清除率。而现有“化学小分子药物不会影响单克隆抗体药物消除”的学术观点无法解释该现象。已有研究证实，新生儿抗体可结晶片段受体（FcRn）可以保护单克隆抗体药物免遭降解消除。并且我们发现，FcRn可经蛋白酶体糜蛋白酶样活性催化降解代谢，而甲氨蝶呤和雷公藤甲素则可显著抑制蛋白酶体糜蛋白酶样活性。我们推测“甲氨蝶呤和雷公藤甲素通过抑制蛋白酶体糜蛋白酶样活性去抑制FcRn降解，从而提高FcRn含量，保护更多单克隆抗体药物免遭降解消除”。因此，本研究提出“化学小分子药物可通过‘蛋白酶体糜蛋白酶样活性-FcRn’通路影响单克隆抗体药物消除”的科学假说，探索化学小分子药物影响单克隆抗体药物消除的作用机制；并依据该假说建立基于化学小分子药物联用的单克隆抗体药物群体药动学模型。该研究可以为单克隆抗体药物的临床合理用药提供科学依据。

Some small molecule drugs including methotrexate and triptolide significantly reduce the clearance of monoclonal antibodies (mAbs) when small molecule drugs are concomitantly used with mAbs. However, this result conflicts with the classical viewpoint that small molecule drugs seldom affect the elimination of mAbs. It has been proved that neonatal Fc receptor (FcRn) can protect mAbs from lysosomal degradation. Furthermore, the degradation of FcRn is found to be catalyzed by proteasomal chymotrypsin like activity, and methotrexate and triptolide can inhibit the proteasomal chymotrypsin like activity. We speculated that methotrexate and triptolide might slow down the degradation of FcRn by suppressing the proteasomal chymotrypsin-like activity, thereby more FcRn was survived and FcRn could protect more mAbs from lysosomal degradation. In this study, we explored the mechanism by which small molecule drugs affected the elimination of mAbs, and we proposed a hypothesis that small molecule drugs might affect the elimination of mAbs based on the pathway of "proteasomal chymotrypsin-like activity-FcRn". In addition, we established a population pharmacokinetic model of mAbs. This study can provide scientific basis for clinical rational use of mAbs.