Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark.
Department of Biomedicine, Aarhus University, 8200 Aarhus, Denmark.
Int J Mol Sci. 2020 Jul 31;21(15):5497. doi: 10.3390/ijms21155497.
The macrophage is a key cell in the pro- and anti-inflammatory response including that of the inflammatory microenvironment of malignant tumors. Much current drug development in chronic inflammatory diseases and cancer therefore focuses on the macrophage as a target for immunotherapy. However, this strategy is complicated by the pleiotropic phenotype of the macrophage that is highly responsive to its microenvironment. The plasticity leads to numerous types of macrophages with rather different and, to some extent, opposing functionalities, as evident by the existence of macrophages with either stimulating or down-regulating effect on inflammation and tumor growth. The phenotypes are characterized by different surface markers and the present review describes recent progress in drug-targeting of the surface marker CD163 expressed in a subpopulation of macrophages. CD163 is an abundant endocytic receptor for multiple ligands, quantitatively important being the haptoglobin-hemoglobin complex. The microenvironment of inflammation and tumorigenesis is particular rich in CD163 macrophages. The use of antibodies for directing anti-inflammatory (e.g., glucocorticoids) or tumoricidal (e.g., doxorubicin) drugs to CD163 macrophages in animal models of inflammation and cancer has demonstrated a high efficacy of the conjugate drugs. This macrophage-targeting approach has a low toxicity profile that may highly improve the therapeutic window of many current drugs and drug candidates.
巨噬细胞是促炎和抗炎反应的关键细胞，包括恶性肿瘤的炎症微环境。因此，目前许多慢性炎症性疾病和癌症的药物开发都集中在巨噬细胞作为免疫治疗的靶点上。然而，这种策略受到巨噬细胞的多效表型的复杂性的影响，巨噬细胞对其微环境高度敏感。这种可塑性导致了许多不同类型的巨噬细胞，它们具有相当不同的、在某种程度上是对立的功能，这一点可以从具有刺激或下调炎症和肿瘤生长作用的巨噬细胞的存在中明显看出。这些表型的特征是不同的表面标记，本综述描述了靶向表达在巨噬细胞亚群中的表面标记 CD163 的药物的最新进展。CD163 是多种配体的丰富内吞受体，其中数量重要的是结合珠蛋白-血红蛋白复合物。炎症和肿瘤发生的微环境富含 CD163 巨噬细胞。在炎症和癌症的动物模型中，使用抗体将抗炎（如糖皮质激素）或杀肿瘤（如阿霉素）药物靶向 CD163 巨噬细胞，已经证明了偶联药物的高疗效。这种巨噬细胞靶向方法具有低毒性特征，可能极大地提高许多现有药物和候选药物的治疗窗口。
