Bevaart Lisette, Goldstein Joel, Vitale Laura, Russoniello Christina, Treml John, Zhang Jun, Graziano Robert F, Leusen Jeanette H W, van de Winkel Jan G J, Keler Tibor
Immunotherapy Laboratory, Department of Immunology, University Medical Centre Utrecht, Lundlaan, Utrecht, The Netherlands.
Br J Haematol. 2006 Feb;132(3):317-25. doi: 10.1111/j.1365-2141.2005.05884.x.
Expression of the type I receptor for Fc domain of immunoglobulin (Ig)G (Fc gammaRI or CD64) is restricted to myeloid effector cells, such as monocytes, macrophages and a subset of dendritic cells. Previous work has indicated a role for Fc gammaRI in antibody-dependent phagocytosis and lysis of tumour cells. We hypothesised that tagging of tumour cells with an anti-Fc gammaRI single chain Fv (sFv) may facilitate targeting to this receptor on effector cells, thereby initiating tumour cytotoxicity. A vector encoding the sFv for an Fc gammaRI-specific antibody (H22), linked to the transmembrane domain of platelet-derived growth factor was constructed. Transfected tumour cells expressed high surface levels of functional H22-sFv, which greatly enhanced susceptibility for phagocytosis and lysis by monocytes and macrophages. The expression of H22-sFv evoked the ability of tumour cells to directly activate monocytes, as evidenced by phosphorylation of mitogen-activated protein kinase and secretion of the inflammatory cytokines interleukin (IL)-1beta, tumour necrosis factor-alpha and IL-6. Moreover, growth of tumour cells in mice expressing H22-sFv was profoundly delayed (or absent) in transgenic mice expressing human Fc gammaRI. These results demonstrated that tumour cells can be readily modified to activate cell effector mechanisms, a strategy that may be useful for in vivo targeting in patients.
免疫球蛋白（Ig）G的Fc结构域的I型受体（FcγRI或CD64）的表达仅限于髓系效应细胞，如单核细胞、巨噬细胞和一部分树突状细胞。先前的研究表明FcγRI在抗体依赖性吞噬作用和肿瘤细胞裂解中发挥作用。我们推测用抗FcγRI单链Fv（sFv）标记肿瘤细胞可能有助于靶向效应细胞上的该受体，从而引发肿瘤细胞毒性。构建了一种载体，其编码与血小板衍生生长因子的跨膜结构域相连的FcγRI特异性抗体（H22）的sFv。转染的肿瘤细胞在表面高水平表达功能性H22-sFv，这大大增强了其对单核细胞和巨噬细胞吞噬作用和裂解的敏感性。H22-sFv的表达引发了肿瘤细胞直接激活单核细胞的能力，有丝分裂原活化蛋白激酶的磷酸化以及炎性细胞因子白细胞介素（IL）-1β、肿瘤坏死因子-α和IL-6的分泌证明了这一点。此外，在表达人FcγRI的转基因小鼠中，表达H22-sFv的肿瘤细胞在小鼠体内的生长被显著延迟（或不存在）。这些结果表明，肿瘤细胞可以很容易地被修饰以激活细胞效应机制，这一策略可能对患者体内靶向治疗有用。
