Nanobody-Based Targeting of the Macrophage Mannose Receptor for Effective In Vivo Imaging of Tumor-Associated Macrophages
Nanobody-Based Targeting of the Macrophage Mannose Receptor for Effective In Vivo Imaging of Tumor-Associated Macrophages
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DOI：
10.1158/0008-5472.can-11-2994
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发表时间：
2012-08-15
期刊：
影响因子：
11.2
通讯作者：
Van Ginderachter, Jo A.
中科院分区：
文献类型：
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作者：
Movahedi, Kiavash;Schoonooghe, Steve;Van Ginderachter, Jo A.
肿瘤相关巨噬细胞()是肿瘤间质的重要组成部分，具有多种促肿瘤活性。位于低氧肿瘤区域的强促血管生成TAMs高表达巨噬细胞甘露糖受体(MMR，CD206)。在这项研究中，我们使用纳米体来靶向MMR+TAMs，这些纳米体是来自驼科重链抗体的单域抗原结合片段。MMR特异性纳米体染有TAMs在体外肺和乳腺肿瘤单细胞悬液中，静脉注射99m标记的抗MMR纳米体体内成功靶向肿瘤。纳米体的保留是受体专一性的，在MMR缺陷小鼠中不存在。重要的是，联合注射过量的未标记的二价抗MMR纳米体可将纳米体在肿瘤外器官中的积聚减少到背景水平，而不会影响肿瘤的摄取。在肿瘤内，TC-99m标记的纳米体专门标记MMR+TAMS，因为CCR2缺陷小鼠含有较少的TAMS，显示出显著的肿瘤摄取减少。此外，抗MMR纳米体聚积在缺氧区，从而靶向促血管生成的MMR+TAMs。综上所述，我们的发现提供了临床前的概念证据，即抗MMR纳米抗体可以在体内选择性地靶向和成像亚群。癌症资源；72(16)；4165-77。(C)2012年AACR。
Tumor-associated macrophages (TAM) are an important component of the tumor stroma and exert several tumor-promoting activities. Strongly pro-angiogenic TAMs that reside in hypoxic tumor areas highly express macrophage mannose receptor (MMR, CD206). In this study, we targeted MMR+ TAMs using nanobodies, which are single-domain antigen-binding fragments derived from Camelidae heavy-chain antibodies. MMR-specific nanobodies stained TAMs in lung and breast tumor single-cell suspensions in vitro, and intravenous injection of Tc-99m-labeled anti-MMR nanobodies successfully targeted tumor in vivo. Retention of the nanobody was receptor-specific and absent in MMR-deficient mice. Importantly, co-injection of excess unlabeled, bivalent anti-MMR nanobodies reduced nanobody accumulation in extratumoral organs to background levels, without compromising tumor uptake. Within tumors, the Tc-99m-labeled nanobodies specifically labeled MMR+ TAMs, as CCR2-deficient mice that contain fewer TAMs showed significantly reduced tumor uptake. Further, anti-MMR nanobodies accumulated in hypoxic regions, thus targeting pro-angiogenic MMR+ TAMs. Taken together, our findings provide preclinical proof of concept that anti-MMR nanobodies can be used to selectively target and image TAM subpopulations in vivo. Cancer Res; 72(16); 4165-77. (C) 2012 AACR.