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毒理学蛋白质生物标志物分析——一项在食蟹猴中进行的为期一周的单剂量静脉输注毒性和毒代动力学研究，使用一种针对卵巢癌的抗体-细胞毒性偶联物。

Toxicological protein biomarker analysis--an investigative one-week single dose intravenous infusion toxicity and toxicokinetic study in cynomolgus monkeys using an antibody-cytotoxic conjugate against ovarian cancer.

作者信息

Hsieh Frank Y, Tengstrand Elizabeth, Li Lily Y, Huang Yuling N, Milton Mark N, Silverman Lee, Alden Carl, Miwa Gerald, Lee Frank

机构信息

Nextcea, Inc., 110 Hartwell Avenue, Lexington, Massachusetts 02421, USA.

出版信息

Pharm Res. 2008 Jun;25(6):1309-17. doi: 10.1007/s11095-007-9485-z.

DOI:10.1007/s11095-007-9485-z
PMID:18060481
Abstract

INTRODUCTION

Antibody-cytotoxic conjugates are complex novel therapeutic agents whose toxicological properties are not presently well understood. The objective of this study was to identify toxicological markers in serum that correlate with MLN8866 (an antibody-cytotoxic conjugate) exposure and related pathological events in monkeys.

MATERIALS AND METHODS

Cynomolgus monkeys were treated once with 5, 15, or 30 mg/kg MLN8866 via a 20 min intravenous infusion. MLN8866 exposure (Cmax and AUCO-4 day) was determined by quantifying MLN8866 levels in serum.

RESULTS

The increase in MLN8866 exposure was approximately dose proportional. Two acute phase proteins in serum (serum amyloid A and haptoglobin) were correlated with MLN8866 exposure and toxicological outcomes (e.g., erythropoiesis and leucopoiesis).

摘要

引言

抗体-细胞毒性缀合物是复杂的新型治疗剂，其毒理学特性目前尚未完全了解。本研究的目的是确定血清中的毒理学标志物，这些标志物与MLN8866（一种抗体-细胞毒性缀合物）的暴露以及猴子体内相关的病理事件相关。

材料与方法

食蟹猴通过20分钟静脉输注接受一次5、15或30mg/kg的MLN8866治疗。通过定量血清中的MLN8866水平来确定MLN8866的暴露量（Cmax和AUCO-4天）。

结果

MLN8866暴露量的增加与剂量大致成正比。血清中的两种急性期蛋白（血清淀粉样蛋白A和触珠蛋白）与MLN8866暴露量和毒理学结果（如红细胞生成和白细胞生成）相关。

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