Würflein D, Dechant M, Stockmeyer B, Tutt A L, Hu P, Repp R, Kalden J R, van de Winkel J G, Epstein A L, Valerius T, Glennie M, Gramatzki M
Department of Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany.
Cancer Res. 1998 Jul 15;58(14):3051-8.
Promising results from clinical trials have led to renewed interest in effector mechanisms operating in antibody-based therapy of leukemia and lymphoma. We tested a panel of B-cell antibodies from the Sixth Human Leukocyte Differentiation Antigen workshop for their capacity to mediate antibody-dependent cellular cytotoxicity, often considered to be one of the most potent effector mechanisms in vivo. As effector cells, mononuclear cells and polymorphonuclear (PMN) cells from healthy donors were compared with Fc gammaRI (CD64)-expressing PMN cells from patients receiving granulocyte colony-stimulating factor (G-CSF) treatment. Of the 29 IgG workshop antibodies binding most strongly to the tested malignant human B-cell lines, only 3 consistently induced target cell lysis. These three antibodies were determined to be HLA DR reactive. Experiments with a panel of HLA class II antibodies showed the involvement of individual Fc gamma receptors on effector cells to be strongly dependent on the antibody isotype. We then compared killing mediated by chimeric IgG1 antibodies with that from Fc gammaRI-directed bispecific antibodies, targeting classical HLA class II, or the Lym-1 and Lym-2 antigens. The latter two are variant forms of HLA class II, which are highly expressed on the surface of malignant B cells but which are found only at low levels in normal cells. With blood from G-CSF-treated donors, bispecific antibodies showed enhanced killing compared to their chimeric IgG1 derivatives, because they were more effective in recruiting Fc gammaRI-expressing PMN cells. G-CSF- and Fc gammaRI-directed bispecific antibodies to HLA class II, therefore, seem to be an attractive combination for lymphoma therapy.
临床试验取得的 promising 结果引发了人们对白血病和淋巴瘤抗体治疗中效应机制的新兴趣。我们测试了第六届人类白细胞分化抗原研讨会的一组 B 细胞抗体介导抗体依赖性细胞毒性的能力，抗体依赖性细胞毒性通常被认为是体内最有效的效应机制之一。作为效应细胞，将健康供体的单核细胞和多形核（PMN）细胞与接受粒细胞集落刺激因子（G-CSF）治疗的患者的表达 FcγRI（CD64）的 PMN 细胞进行了比较。在与测试的恶性人类 B 细胞系结合最紧密的 29 种 IgG 研讨会抗体中，只有 3 种始终诱导靶细胞裂解。确定这三种抗体具有 HLA DR 反应性。一组 HLA II 类抗体的实验表明，效应细胞上各个 Fcγ受体的参与强烈依赖于抗体同种型。然后，我们比较了嵌合 IgG1 抗体与靶向经典 HLA II 类、Lym-1 和 Lym-2 抗原的 FcγRI 导向双特异性抗体介导的杀伤作用。后两者是 HLA II 类的变体形式，在恶性 B 细胞表面高度表达，但在正常细胞中仅以低水平存在。对于来自 G-CSF 治疗供体的血液，双特异性抗体与其嵌合 IgG1 衍生物相比显示出增强的杀伤作用，因为它们在募集表达 FcγRI 的 PMN 细胞方面更有效。因此，G-CSF 和 FcγRI 导向的针对 HLA II 类的双特异性抗体似乎是淋巴瘤治疗的有吸引力的组合。
