“多肽-受体”介导177Lu治疗的药效学机制探索

Peptide Receptor Radionuclide Therapy (PRRT) is a research focus worldwide in recent years. With the success of clinical trial on 177Lu-DOTATATE therapy in neuroendocrine tumors and 177Lu-PSMA-617 therapy in castration-resistant prostate cancer, many new drugs are emerging to maximize the efficacy and minimize the toxicity. In the preliminary dosimetry study of novel theranostic agents that conjugated a truncated Evans Blue (EB) molecule onto TATE or PSMA, we found there were challenges on the pharmacodynamics of 177Lu therapy, which might be an interesting topic for further investigation. The aim of this study is to investigate the pharmacodynamic mechanism of peptide-receptor mediated 177Lu therapy through evaluating the mouse xenografts models of neuroendocrine tumors and prostate cancer, and as well, analyzing the dynamic imaging data and treatment response to 177Lu-DOTA-EB-TATE and 177Lu-EB-PSMA-617 in patient volunteers with refractory neuroendocrine tumors and castration-resistant prostate cancer, respectively. The study will explore the pharmacological mechanism of 177Lu therapy by comparing these EB-modified radiopharmaceuticals with the original theranostic agents and establishing the corresponding pharmacokinetic/pharmacodynamic models. And then, lay the foundation for further development and clinical transformation of new drug for 177Lu therapy in the future.

“多肽-受体”介导的放射性核素治疗（Peptide Receptor Radionuclide Therapy，PRRT）是近年来国际国内研究的前沿热点。特别是随着177Lu-DOTATATE治疗和177Lu-PSMA-617治疗临床研究的成功及治疗效果被广泛认可，各种优化设计和改进疗效的177Lu治疗新药不断涌现。申请人研究团队前期对用伊文思兰（EB）改构获得的新型177Lu治疗药物177Lu-EB-TATE和177Lu-EB-PSMA开展了初步的剂量学和药效学研究。针对所发现的药效学难题，本项目拟通过对神经内分泌肿瘤和前列腺癌的裸鼠肿瘤模型研究，以及对因难治性神经内分泌肿瘤或前列腺癌行177Lu治疗志愿者的动态显像与疗效评估数据进行深入系统分析，探索“多肽-受体”介导177Lu治疗的药效学机制，建立相应的药代动力学/药效学模型，为进一步推进177Lu治疗新药研发和临床转化打下基础。

1、研究背景.以SSTR和PSMA为靶点的放射性核素治疗一直是国际临床医学研究的热点前沿。申请人团队前期利用伊文思兰改构获得了新型核素治疗药物DOTA-EB-TATE和EB-PSMA。本项目拟探索两种药物介导177Lu治疗的药效学机制，建立相应的药代动力学/药效学模型，为进一步推进177Lu治疗新药研发和临床转化打下基础。.2、主要内容.①利用神经内分泌肿瘤和前列腺癌的裸鼠肿瘤模型，分别进行177Lu-DOTA-EB-TATE和177Lu-EB-PSMA的“剂量-效应”研究。.②招募难治性神经内分泌肿瘤和前列腺癌志愿者，分别行177Lu-DOTA-EB-TATE和177Lu-EB-PSMA治疗，开展药效学研究。.3、重要结果.①177Lu-DOTA-EB-TATE和177Lu-EB-PSMA可与血浆白蛋白结合，延长血液滞留，减缓排出，使得肿瘤组织充分吸收药物，提高了核素利用率。.②较低剂量177Lu-DOTA-EB-TATE和177Lu-EB-PSMA能达到与较高剂量177Lu-DOTATATE和177Lu-PSMA-617相近的疗效。.4、关键数据.①177Lu-DOTA-EB-TATE在神经内分泌肿瘤组织中的有效吸收剂量是177Lu-DOTATATE的7.9倍，在肾脏及骨髓的有效吸收剂量分别是后者的18.2倍和3.2倍；1.89 GBq可能是基于177Lu-DOTA-EB-TATE治疗的理想剂量，但3.97 GBq 177Lu-DOTA-EB-TATE治疗仍具有较好的安全性。.②177Lu-EB-PSMA在前列腺癌组织中的有效吸收剂量是177Lu-PSMA-617的3.02倍，在肾脏及骨髓的有效吸收剂量约为后者的6倍；2.22 GBq可能是基于177Lu-EB-PSMA的理想剂量；平均2疗程2.02 GBq 177Lu-EB-PSMA治疗的PSA应答率及毒副作用基本与4-6疗程的7.40 GBq 177Lu-PSMA-617治疗相当。.5、科学意义.本研究初步解决了临床177Lu靶向治疗在药效学方面的基础难题，建立了针对性的177Lu靶向治疗药代动力学/药效学模型，这有助于在今后的临床实践中降低医疗成本，具有较高的研究价值。