放射性同位素示踪技术在生物药临床研究中的应用

Application of radioisotope tracer technology in the clinical research of biological drugs

目的探讨放射性同位素示踪技术在生物药临床研究中的应用价值。方法对3名健康志愿者静脉滴注131I标记的国际一类新药美珀珠单抗,通过测定14 d内不同时间点血样与尿样的放射性浓度,评价美珀珠单抗在健康人体内的药代动力学性质(试验1)。对6名健康志愿者静脉注射68Ga标记的核酸适配体Sgc8,分别于不同时间点行正电子发射型计算机断层显像(PET/CT),通过测定不同器官对68Ga Sgc8的标准摄取值,评价68Ga⁃Sgc8在健康人体内的生物学分布(试验2)。对9例疑似神经内分泌瘤患者静脉注射99mTc奥曲肽,4 h后行单光子发射和X线计算机断层扫描(SPECT/CT),测定感兴趣区放射性摄取水平;结合患者活检组织生长抑素受体亚型2(SSTR2)免疫组化染色结果,评价99mTc⁃奥曲肽对SSTR2的亲和性和靶向性(试验3)。结果纳入试验1的3名健康志愿者均为男性,年龄分别为28、45和25岁;131I⁃美珀珠单抗注射剂量分别为21.0、25.9和17.6 mg,放射性活度分别为364、420和304 MBq。纳入试验2的6名健康志愿者中男性和女性各3名,年龄(46±11)岁,范围35~63岁;放射性活度为(80±7)MBq,范围69~87 MBq。纳入试验3的9例疑似神经内分泌瘤患者中男性5例、女性4例,年龄(54±10)岁,范围39~69岁;放射性活度为(777±74)MBq,范围740~925 MBq。静脉滴注131I⁃美珀珠单抗后,受试者血液放射性浓度在1.5 h达峰值,131I⁃美珀珠单抗主要与血细胞结合,其全血清除半衰期为420 h;尿液放射性浓度在16~24 h达峰值,24 h后逐渐降低。静脉注射68Ga⁃Sgc8后即刻放射性信号由强至弱的器官依次为膀胱、肾脏、心脏、子宫、肝脏、脾脏、胆囊、大肠和肺;注射药物后3 h内心脏的清除速率最快,子宫、肾脏和肝脏次之,脾脏和胆囊的清除速率较慢,大肠和肺的清除速率最慢。9例患者静脉注射99mTc⁃奥曲肽后4 h体内均有放射性异常浓聚,免疫组化染色结果示SSTR2呈强阳性表达,表明99mTc⁃奥曲肽对SSTR2有良好的亲和性和靶向性。安全性测试结果显示,试验1中1名受试者静脉滴注131I⁃美珀珠单抗后1个月出现碘相关甲状腺功能亢进,无干预持续监测8个月后恢复正常;其余受试者均未发生不良反应。结论放射性同位素示踪技术可无创、动态、可视化地评价生物药在人体内的药代动力学性质、生物学分布及靶向性,安全性良好,在生物药的临床评价中具有重要的应用价值。

Objective To explore the application value of radioisotope tracer technology in clinical research of biological drugs.Methods The pharmacokinetic properties of mepuzumab in healthy volun⁃teers were evaluated by measuring the radioactive concentrations of iodine in blood and urine samples of 3 healthy volunteers at different time points within 14 days after intravenous infusion of 131I⁃labeled internation⁃al class I new drug mepuzumab(Trial 1).Positron emission computed tomography(PET/CT)was per⁃formed on 6 healthy volunteers after intravenous injection of 68Ga⁃labeled nucleic acid aptamer Sgc8,and the standard uptake values of 68Ga⁃Sgc8 in different organs were measured to evaluate its biodistribution in healthy humans(Trial 2).Nine patients with suspected neuroendocrine tumors underwent single photon emis⁃sion and X⁃ray computed tomography(SPECT/CT)4 hours after intravenous injection of 99mTc⁃labeled octreo⁃tide to determine the radioactive uptake level in the regions of interest;the affinity and targeting of 99mTc⁃labeled octreotide to somatostatin receptor subtype 2(SSTR2)were evaluated in combination with the immu⁃nohistochemical staining results of SSTR2 in patients′biopsy tissues(Trial 3).Results The 3 healthy volunteers included in Trial 1 were male,aged 28,45,and 25 years respectively;the injection doses of 131I⁃labeled mepuzumab were 21.0,25.9,and 17.6 mg,and the injection doses of radioactivity were 364,420,and 304 MBq,respectively.Among the 6 healthy volunteers included in Trial 2,3 were male and 3 were female,with an age of(46±11)years,ranging from 35 to 63 years.The dose of radioactivity injected was(80±7)MBq,ranging from 69 to 87 MBq.Among the 9 patients included in Trial 3,5 were male and 4 were female,with an age of(54±10)years,ranging from 39 to 69 years.The dose of radioactivity injected was(777±74)MBq,ranging from 740 to 925 MBq.After intravenous infusion of 131I⁃labeled mepuzumab,the blood radioactivity concentration reached the peak 1.5 hours later.131I⁃labeled mepuzumab mainly bound to blood cells,and its whole⁃blood clearance half⁃life was 420 hours.The urine radioactivity concentration reached the peak 16⁃24 hours after administration and then gradually decreased after 24 hours of adminis⁃tration.After intravenous injection of 68Ga⁃labeled Sgc8,the organs with strong to weak radioactive signals were bladder,kidney,heart,uterus,liver,spleen,gallbladder,large intestine and lung.Within 3 hours after drug administration,the clearance rate was fastest in heart,followed by uterus,kidney,and liver;the clearance rate was slower in spleen and gallbladder and were slowest in large intestine and lung.All of the 9 patients had abnormal radioactivity accumulation 4 hours after intravenous injection of 99m Tc⁃labeled octreotide and the immunohistochemical staining results of biopsy tissues showed strong positive expression of SSTR2,indi⁃cating that 99m Tc⁃labeled octreotide had good affinity and targeting to SSTR2.The safety evaluation showed that in Trail 1,one subject developed iodine⁃related hyperthyroidism one month after intravenously infu⁃sion of 131I⁃labeled mepuzumab,which returned to normal after 8 months of continuous monitoring without intervention.No adverse reactions occurred in other subjects.Conclusions Radioisotope tracer technology can noninvasively,dynamically,and visually evaluate the pharmacokinetics,biological distribution,and targeting of biological drugs in human body.It has good safety and great application value in the clinical evaluation of biological drugs.