Genentech Research and Early Development, South San Francisco, CA 94080, USA.
Br J Pharmacol. 2013 Jan;168(2):445-57. doi: 10.1111/j.1476-5381.2012.02138.x.
The 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.
A 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.
The 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.
Our 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.
抗体药物偶联物（ADC）的成功取决于正常组织和病理组织之间差异表达所产生的治疗窗口。识别和可视化正常组织中目标表达的能力，可以揭示药代动力学特征中观察到的靶介导清除的原因。TENB2 是一种与低分化和雄激素非依赖性肿瘤类型进展相关的前列腺癌靶标，针对 TENB2 的 ADC 是候选治疗药物。本研究的目的是定位 TENB2 在正常组织中的抗原表达，从而阐明靶介导清除的潜在原因。
使用放射性标记的抗 TENB2 ADC 在小鼠中进行了一系列药代动力学、组织分布和质量平衡研究。这些数据通过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得到补充。
肠道被确定为一个可饱和和特异性的抗原清除器官，至少在一定程度上导致抗 TENB2 抗体及其药物偶联物在啮齿动物中快速的靶介导清除。作为概念验证，我们还使用 LuCaP 77 移植小鼠模型在体内证明了 ADC 在肿瘤环境中的选择性分布。尽管存在抗原清除器官，但仍观察到高肿瘤摄取，并且通过抗原阻断证实了抗原特异性。
我们的发现为抗 TENB2 抗体及其相应药物偶联物的靶介导清除提供了解剖位置和生物学解释。进一步的研究可能有助于解决抗原在正常和病理组织中的表达对 ADC 分布的相对贡献。
