融合蛋白rh-TNT-IL-2临床前药代动力学的研究
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摘要
目的:研究创新药rhTNT-IL-2融合蛋白临床前药代动力学,为药物进行临床前药理学和毒理学研究,以及为临床合理用药的安全性和有效性研究提供依据。
方法:(1)采用同位素标记示踪法结合三氯醋酸(TCA)沉淀法和单光子发射计算机断层扫描(SPECT)技术研究~(125)I-rhTNT-IL-2的药代动力学。(2)用氯胺-T(Ch-T)法对rhTNT-IL-2融合蛋白进行~(125)I标记,标记物的放射化学纯度测定采用纸色谱法和高效液相色谱法。TCA沉淀法用于分离rhTNT-IL-2融合蛋白和它的代谢物。(3)同位素示踪法测量三种不同剂量的rhTNT-IL-2在大鼠和猕猴体内的血药浓度随时间的变化。大鼠注射剂量分别为2500μg·kg~(-1)、250μg·kg~(-1)和125μg·kg~(-1),猕猴的注射剂量分别为1250μg·kg~(-1)、125μg·kg~(-1)和63μg·kg~(-1)。用DAS1.0软件拟合大鼠和猕猴的药物代谢数学模型,并计算它们的药代动力学参数。(4)~(125)I-rhTNT-IL-2在大鼠体内的分布采用放射性示踪法,而~(125)I-rhTNT-IL-2在猕猴体内的分布采用SPECT显像和感兴趣区(ROI)分析技术,半定量测量。(5)收集大鼠和猕猴不同时间段排出的尿和粪,测量它们的放射性,计算不同时间内累积排出百分数。
结果:(1)~(125)I-rhTNT-IL-2标记物的放射化学纯度大于95%,Ch-T法标记~(125)I对rhTNT-IL-2的物理化学性质和生物活性影响不大。(2)测量方法的精密度在0.8%~18.5%范围,准确度在81.6%~108.4%范围,各批试验的TCA沉淀前后的标准曲线呈线性(r>0.996),标准曲线的浓度覆盖了样品测量的范围,~(125)I-rhTNT-IL-2的TCA沉淀率基本都大于90%,而TCA沉淀对~(125)I-非特异性吸附仅为5.3%。放射性标记示踪法结合TCA沉淀法开展rhTNT-IL-2药代动力学研究,方法是可行的。(3)三种不同剂量的~(125)I-rhTNT-IL-2单次静脉注射后在大鼠和猕猴体内的动力学过程都符合三室模型,在大鼠体内的T_(1/2)α、T_(1/2)β和T_(1/2)γ分别为1.77h~3.03 h、24.58h~28.88 h和82.17h~114.09 h,在猕猴体内的T_(1/2)α、T_(1/2)β和T_(1/2)γ分别为1.87h~3.33h、9.82h~ 17.38h和37.84h~68.38h。血药浓度-时间曲线下面积(AUC)和注射剂量有明显的线性关系(r=0.999)。血浆中药物以原形药存在为主。(4)代谢初期,~(125)I-rhTNT-IL-2主要分布在猕猴的肝、脾和肾等脏器,给药48h后,除甲状腺和膀胱(含尿)内放射性水平稍高外,其余脏器分布均较少。~(125)I-rhTNT-IL-2
Objective: To investigate the preclinical pharmacokinetics, bioditribution and excretion of a recombinant fusion protein rhTNT-IL-2, which is helpful for the investigation of its preclinical toxicology, preclinical pharmacodynamics and clinical experiment.
Methods: (1) The pharmacokinetics, bioditribution and excretion of rhTNT-IL-2 were investigated with radiolabels combined with Trichloroacetic acid (TCA) precipitation or single photon emission computed tomography (SPECT). (2) rhTNT-IL-2 were labeled with ~(125)I by Chloramine-T (Ch-T) method. Paper chromatography and high performance liquid chromatography (HPLC) were used to determine their radiochemical purities. TCA precipitation method was used to separate the fusion protein from its metabolite, and radioactivity of all samples was counted by a dual-window gamma counter. (3) Wistar rat and macaque were used in the trial. A group of Wistar rats and macaques were injected with ~(125)I-rhTNT-IL-2 at 2500μg·kg~(-1), 250μg·kg~(-1), 125μg·kg~(-1)and 1250μg·kg~(-1), 125μg·kg~(-1), 63μg·kg~(-1) respectively. After the injection, serial blood samples were withdrawn and determinated. The blood clearance rates of ~(125)I-rhTNT-IL-2 were illustrated as its concentration over time. The main parameters of pharmacokinetics were calculated by DAS1.0 software. (4) The biodistribution of ~(125)I-rhTNT-IL-2 in rat was determinated by detecting the radioactivity of their organs, and that in macaque was determinated with SPECT and region of interest (RIO) technique. (4) The urine and feces of administrated rats and macaques were collected during a certain interval and radioactivity of aliquot urine and feces was counted. The cumulated excretion fractions of rats and macaques were calculated.
Results: (1) The radiochemical purities of ~(125)I-rhTNT-IL-2 were more than 95%. There is no change of its character after labeled with iodine-125. (2) The precision of
方法:(1)采用同位素标记示踪法结合三氯醋酸(TCA)沉淀法和单光子发射计算机断层扫描(SPECT)技术研究~(125)I-rhTNT-IL-2的药代动力学。(2)用氯胺-T(Ch-T)法对rhTNT-IL-2融合蛋白进行~(125)I标记,标记物的放射化学纯度测定采用纸色谱法和高效液相色谱法。TCA沉淀法用于分离rhTNT-IL-2融合蛋白和它的代谢物。(3)同位素示踪法测量三种不同剂量的rhTNT-IL-2在大鼠和猕猴体内的血药浓度随时间的变化。大鼠注射剂量分别为2500μg·kg~(-1)、250μg·kg~(-1)和125μg·kg~(-1),猕猴的注射剂量分别为1250μg·kg~(-1)、125μg·kg~(-1)和63μg·kg~(-1)。用DAS1.0软件拟合大鼠和猕猴的药物代谢数学模型,并计算它们的药代动力学参数。(4)~(125)I-rhTNT-IL-2在大鼠体内的分布采用放射性示踪法,而~(125)I-rhTNT-IL-2在猕猴体内的分布采用SPECT显像和感兴趣区(ROI)分析技术,半定量测量。(5)收集大鼠和猕猴不同时间段排出的尿和粪,测量它们的放射性,计算不同时间内累积排出百分数。
结果:(1)~(125)I-rhTNT-IL-2标记物的放射化学纯度大于95%,Ch-T法标记~(125)I对rhTNT-IL-2的物理化学性质和生物活性影响不大。(2)测量方法的精密度在0.8%~18.5%范围,准确度在81.6%~108.4%范围,各批试验的TCA沉淀前后的标准曲线呈线性(r>0.996),标准曲线的浓度覆盖了样品测量的范围,~(125)I-rhTNT-IL-2的TCA沉淀率基本都大于90%,而TCA沉淀对~(125)I-非特异性吸附仅为5.3%。放射性标记示踪法结合TCA沉淀法开展rhTNT-IL-2药代动力学研究,方法是可行的。(3)三种不同剂量的~(125)I-rhTNT-IL-2单次静脉注射后在大鼠和猕猴体内的动力学过程都符合三室模型,在大鼠体内的T_(1/2)α、T_(1/2)β和T_(1/2)γ分别为1.77h~3.03 h、24.58h~28.88 h和82.17h~114.09 h,在猕猴体内的T_(1/2)α、T_(1/2)β和T_(1/2)γ分别为1.87h~3.33h、9.82h~ 17.38h和37.84h~68.38h。血药浓度-时间曲线下面积(AUC)和注射剂量有明显的线性关系(r=0.999)。血浆中药物以原形药存在为主。(4)代谢初期,~(125)I-rhTNT-IL-2主要分布在猕猴的肝、脾和肾等脏器,给药48h后,除甲状腺和膀胱(含尿)内放射性水平稍高外,其余脏器分布均较少。~(125)I-rhTNT-IL-2
Objective: To investigate the preclinical pharmacokinetics, bioditribution and excretion of a recombinant fusion protein rhTNT-IL-2, which is helpful for the investigation of its preclinical toxicology, preclinical pharmacodynamics and clinical experiment.
Methods: (1) The pharmacokinetics, bioditribution and excretion of rhTNT-IL-2 were investigated with radiolabels combined with Trichloroacetic acid (TCA) precipitation or single photon emission computed tomography (SPECT). (2) rhTNT-IL-2 were labeled with ~(125)I by Chloramine-T (Ch-T) method. Paper chromatography and high performance liquid chromatography (HPLC) were used to determine their radiochemical purities. TCA precipitation method was used to separate the fusion protein from its metabolite, and radioactivity of all samples was counted by a dual-window gamma counter. (3) Wistar rat and macaque were used in the trial. A group of Wistar rats and macaques were injected with ~(125)I-rhTNT-IL-2 at 2500μg·kg~(-1), 250μg·kg~(-1), 125μg·kg~(-1)and 1250μg·kg~(-1), 125μg·kg~(-1), 63μg·kg~(-1) respectively. After the injection, serial blood samples were withdrawn and determinated. The blood clearance rates of ~(125)I-rhTNT-IL-2 were illustrated as its concentration over time. The main parameters of pharmacokinetics were calculated by DAS1.0 software. (4) The biodistribution of ~(125)I-rhTNT-IL-2 in rat was determinated by detecting the radioactivity of their organs, and that in macaque was determinated with SPECT and region of interest (RIO) technique. (4) The urine and feces of administrated rats and macaques were collected during a certain interval and radioactivity of aliquot urine and feces was counted. The cumulated excretion fractions of rats and macaques were calculated.
Results: (1) The radiochemical purities of ~(125)I-rhTNT-IL-2 were more than 95%. There is no change of its character after labeled with iodine-125. (2) The precision of
引文
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[2] Paolo de Paoli. Immunological Effects of Interleukin-2 Therapy in Human Immunodeficiency Virus-Positive Subjects. Clinical and Diagnostic Laboratory Immunology. 2001,8(4): 671~677
[3] 傅云峰,吕卫国.白介素2受体及其与肿瘤免疫逃逸.上海免疫学杂志.2002, 22(2):132~134
[4] Donohue, J.H., Rosenberg, S.A.. The fate of interleukin-2 after in vivo administration. J. Immunol. 1983,130: 2203.
[5] Siegel J.P., Puri R.K.. Interleukin-2 toxicity. J. Clin. Oncol.. 1991,9:694~698.
[6] 高凌,潘尚仁,杨敏,等. 重组人白细胞介素-2在小鼠体内的药代动力学及组织分布. 中国药科大学学报.1997,28(4):228~232
[7] 刘洪涛,尚明美,宋海峰.聚乙二醇化修饰对蛋白多肽药物药代动力学的影响.生物技术通讯.2005,16(5):577~579
[8] Paolo Caliceti, Francesco M. Veronese. Pharmacokinetic and biodistribution properties of poly(ethylene glycol)–protein conjugates. Advanced Drug Delivery Reviews,2003,55: 1261~1277
[9] Kenneth D. Hinds , Sung Wan Kim. Effects of PEG conjugation on insulin properties. Advanced Drug Delivery Reviews. 2002, 54:505~530
[10] Jin Y,Li J,Rong LF,el a1.Pharmacokinetics and tissue distribution of 5-fluorouracil encapsulated by galactosylceramide liposomes in mice . Acta Pharmacol Sin. 2005,26(2):250~254.
[11] Andrew P. Chapman. PEGylated antibodies and antibody fragments for improved therapy: a review. Advanced Drug Delivery Reviews. 2002, 54:531~545
[12] Lee LS,Connover C,Whihlow M,et o1.Prolonged circulating lives of single-chain Fv proteins conjugated with polyethylene glycol: a comparison of conjugation chemistries and compounds.Bioconjug. Chem. 1999,10:973~999
[13] 张云龙,谢英,王会娟,等. 超氧化物歧化酶脂质体在大鼠体内的药代动力学和组织分布. 药学学报. 2005,40(2):173~177
[14] Neville ME, Richau KW, Boli LT,et al. A comparison of biodistribution of liposomal and soluble IL-2 by a new method based on time-resolved fluorometry of europium. Cytokine, 2000,12:1702-1711
[15] Luisa Corvo M,Jorge JC,van’t Hof R,et a1.Superxide dismutase entrapped in long-circulating liposomes:formulation design and therapeutic activity in rat adjuvant authritis.Biochim Biophys Acta. 2002,1564(1):227~236
[16] 田军,印春华,蒋雪涛. 白细胞介素2 脂质体家兔体内药代动力学研究. 第二军医大学学报. 1997, 18 (5)∶488~490
[17] Xiang J. Targeting cytokines to tumors to induce active antitumor immune responses by recombinant fusion proteins. Hum Antibodies.1999,9:23~36.
[18] Lode HN, Reisfeld RA. Targeted cytokines for cancer immunotherapy.Immunol Res. 2000,21:279~288.
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