Antiangiogenic chimeric anti-endoglin (CD105) antibody: pharmacokinetics and immunogenicity in nonhuman primates and effects of doxorubicin
Antiangiogenic chimeric anti-endoglin (CD105) antibody: pharmacokinetics and immunogenicity in nonhuman primates and effects of doxorubicin
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DOI：
10.1007/s00262-005-0691-4
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发表时间：
2006-02-01
影响因子：
5.8
通讯作者：
Seon, BK
中科院分区：
文献类型：
--
作者：
Shiozaki, K;Harada, N;Seon, BK
我们从鼠抗人内皮糖蛋白（EDG）单克隆抗体（mAb）SN 6 j产生了人IgG 1同种型的人/小鼠嵌合抗体c-SN 6 j，其抑制小鼠中的血管生成、肿瘤生长和转移。我们在多次静脉注射后测定了猴中c-SN 6 j的药代动力学（PK）和免疫原性。通过将c-SN 6 j以每kg体重lmg、3 mg和10 mg的剂量施用至六只猴中进行剂量递增研究。此外，将c-SN 6 j（3 mg/kg）和多柔比星（0.275mg/kg）注射到两只猴子中。c-SN 6 j和阿霉素每周注射两次，持续3周。我们通过顺序靶向c-SN 6 j-Fv的共同和独特型表位来定量血浆c-SN 6 j，从而开发了独特且灵敏的ELISA。ELISA的应用显示，增加c-SN 6 j剂量导致第一次注射后循环c-SN 6 j成比例增加。此外，第一次注射c-SN 6 j的估计曲线下面积（AUC）与剂量成比例。我们在重复注射期间和之后对c-SN 6 j的PK进行了详细分析。我们的PK模型很好地拟合了经验数据。添加多柔比星可调节PK参数。我们开发了两种ELISA来分别测定猴对c-SN 6 j的鼠部分和人部分的免疫应答。有趣的是，鼠部分诱导的免疫应答比人部分弱。阿霉素增强免疫反应。增加c-SN 6 j的剂量增加了c-SN 6 j的血浆水平，但没有增加对c-SN 6 j的免疫应答。
We generated a human/mouse chimeric antibody c-SN6j of human IgG1 isotype from a murine anti-human endoglin (EDG) monoclonal antibody (mAb) SN6j that suppressed angiogenesis, tumor growth and metastasis in mice. We determined pharmacokinetics (PKs) and immunogenicity of c-SN6j in monkeys after multiple i.v. injections. A dose-escalation study was performed by administration of c-SN6j into six monkeys at the dose of 1 mg, 3 mg and 10 mg per kg body weight. In addition, both c-SN6j (3 mg/kg) and doxorubicin (0.275 mg/kg) were injected into two monkeys. c-SN6j and doxorubicin were injected twice a week for 3 weeks. We developed a unique and sensitive ELISA by sequentially targeting the common and idiotypic epitopes of c-SN6j-Fv to quantify plasma c-SN6j. Application of the ELISA showed that increasing the c-SN6j dose resulted in a proportional increase in the circulating c-SN6j after the first injection. In addition, the estimated area under the curve (AUC) for the first injection of c-SN6j is proportional to dose. We carried out detailed analyses of PKs of c-SN6j during and after the repeated injections. Our model of PKs fitted the empirical data well. Addition of doxorubicin modulated the PK parameters. We developed two ELISAs to separately determine the immune responses to the murine part and the human part of c-SN6j in monkeys. Interestingly, the murine part induced a weaker immune response than the human part. Doxorubicin potentiated the immune responses. Increasing the dose of c-SN6j increased plasma levels of c-SN6j but did not increase the immune responses to c-SN6j.