Stockmeyer B, Elsässer D, Dechant M, Repp R, Gramatzki M, Glennie M J, van de Winkel J G, Valerius T
Division of Hematology/Oncology, Department of Medicine III, University of Erlangen-Nürnberg, Krankenhausstrasse 12, D-91054, Erlangen, Germany.
J Immunol Methods. 2001 Feb 1;248(1-2):103-11. doi: 10.1016/s0022-1759(00)00346-x.
Studies with gene-modified mice have recently reinforced the importance of Fc receptor-mediated effector mechanisms for the therapeutic efficacy of rituxan and herceptin - two clinically approved antibodies for the treatment of tumor patients. We investigated Fc receptor-dependent tumor cell killing by mononuclear and granulocytic effector cells - comparing human IgG1 antibodies against CD20 or HER-2/neu with their respective FcgammaRI (CD64)-, FcgammaRIII (CD16)-, or FcalphaRI (CD89)-directed bispecific derivatives. With blood from healthy donors as effector source, human IgG1 and FcgammaRIII (CD16)-directed bispecific antibodies proved most effective in recruiting mononuclear effector cells, whereas tumor cell killing by granulocytes was most potently triggered by FcalphaRI-directed bispecific constructs. Granulocyte-mediated tumor cell lysis was significantly enhanced when blood from G-CSF- or GM-CSF-treated patients was investigated. Interestingly, however, both myeloid growth factors improved effector cell recruitment by different mechanisms, which were furthermore dependent on the tumor target antigen, and on the selected cytotoxic Fc receptor.
近期针对基因改造小鼠开展的研究，进一步证实了Fc受体介导的效应机制对于利妥昔单抗和赫赛汀（两种临床批准用于治疗肿瘤患者的抗体药物）治疗效果的重要性。我们研究了单核细胞和粒细胞效应细胞通过Fc受体依赖途径杀伤肿瘤细胞的情况，比较了针对CD20或HER-2/neu的人IgG1抗体与其相应的靶向FcγRI（CD64）、FcγRIII（CD16）或FcαRI（CD89）的双特异性衍生物。以健康供者的血液作为效应细胞来源时，人IgG1和靶向FcγRIII（CD16）的双特异性抗体在募集单核效应细胞方面最为有效，而靶向FcαRI的双特异性构建体在触发粒细胞杀伤肿瘤细胞方面最为有效。当研究来自接受粒细胞集落刺激因子（G-CSF）或粒细胞-巨噬细胞集落刺激因子（GM-CSF）治疗患者的血液时，粒细胞介导的肿瘤细胞裂解作用显著增强。然而，有趣的是，这两种髓系生长因子通过不同机制改善效应细胞募集，而且这些机制还取决于肿瘤靶抗原以及所选择的细胞毒性Fc受体。
