An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2
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DOI：
10.1111/j.1476-5381.2012.02138.x
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发表时间：
2013-01-01
影响因子：
7.3
通讯作者：
Lin, Kedan
中科院分区：
文献类型：
--
作者：
Boswell, C. Andrew;Mundo, Eduardo E.;Lin, Kedan
背景与目的抗体-药物偶联物（adc）的成功与否取决于正常组织与病理组织之间的差异表达所带来的治疗窗口期。在正常组织中识别和可视化靶表达的能力可以揭示在药代动力学表征中观察到的靶介导清除的原因。TENB2是一种前列腺癌靶点，与低分化和雄激素非依赖性肿瘤类型的进展相关，特异性针对TENB2的adc是候选治疗药物。本研究的目的是定位正常组织中TENB2的抗原表达，从而阐明靶介导清除的潜在原因。实验方法：使用放射性标记的抗tenb2 ADC在小鼠体内进行了一系列的药代动力学、组织分布和质量平衡研究。这些数据由非侵入性单光子发射计算机断层扫描- x射线计算机断层扫描成像和免疫组织化学补充。关键结果：在啮齿类动物中，肠道被鉴定为一个可饱和的特异性抗原库，至少在一定程度上有助于抗tenb2抗体及其药物偶联物的快速靶向清除。作为概念的证明，我们还使用lucap77移植小鼠模型证明了ADC在体内肿瘤环境中的选择性处置。尽管存在抗原库，但仍观察到高肿瘤摄取，抗原特异性通过抗原阻断证实。结论和意义我们的研究结果提供了靶标介导的抗tenb2抗体和相应的药物偶联物清除的解剖位置和生物学解释。进一步的研究可能有助于解决正常和病理组织中抗原表达对ADC处置的相对贡献。
BACKGROUND AND PURPOSEThe success of antibody-drug conjugates (ADCs) depends on the therapeutic window rendered by the differential expression between normal and pathological tissues. The ability to identify and visualize target expression in normal tissues could reveal causes for target-mediated clearance observed in pharmacokinetic characterization. TENB2 is a prostate cancer target associated with the progression of poorly differentiated and androgen-independent tumour types, and ADCs specific for TENB2 are candidate therapeutics. The objective of this study was to locate antigen expression of TENB2 in normal tissues, thereby elucidating the underlying causes of target-mediated clearance.EXPERIMENTAL APPROACHA series of pharmacokinetics, tissue distribution and mass balance studies were conducted in mice using a radiolabelled anti-TENB2 ADC. These data were complemented by non-invasive single photon emission computed tomography - X-ray computed tomography imaging and immunohistochemistry.KEY RESULTSThe intestines were identified as a saturable and specific antigen sink that contributes, at least in part, to the rapid target-mediated clearance of the anti-TENB2 antibody and its drug conjugate in rodents. As a proof of concept, we also demonstrated the selective disposition of the ADC in a tumoural environment in vivo using the LuCaP 77 transplant mouse model. High tumour uptake was observed despite the presence of the antigen sink, and antigen specificity was confirmed by antigen blockade.CONCLUSIONS AND IMPLICATIONSOur findings provide the anatomical location and biological interpretation of target-mediated clearance of anti-TENB2 antibodies and corresponding drug conjugates. Further investigations may be beneficial in addressing the relative contributions to ADC disposition from antigen expression in both normal and pathological tissues.