Stockmeyer B, Dechant M, van Egmond M, Tutt A L, Sundarapandiyan K, Graziano R F, Repp R, Kalden J 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, Erlangen, Germany.
J Immunol. 2000 Nov 15;165(10):5954-61. doi: 10.4049/jimmunol.165.10.5954.
CD20 Abs induce clinical responses in lymphoma patients, but there are considerable differences between individual patients. In (51)Cr release assays with whole blood as effector source, RAJI cells were effectively killed by a mouse/human chimeric IgG1 construct of CD20 Ab 1F5, whereas ARH-77 proved resistant to killing by this Ab. When whole blood was fractionated into plasma, mononuclear cells, or granulocytic effector cells, RAJI cells were effectively killed in the presence of complement-containing plasma, whereas the mature B cell line ARH-77 proved complement resistant. However, with a bispecific Ab (BsAb) against the myeloid receptor for IgA (CD89; FcalphaRI) and CD20, a broad range of B cell lines were effectively killed. FcalphaRI is expressed on monocytes/macrophages, neutrophils, and eosinophils. As the numbers of these effector cells and their functional activity can be enhanced by application of G-CSF or GM-CSF, lysis via (FcalphaRI x CD20) BsAb was significantly enhanced in blood from patients during therapy with these myeloid growth factors. Interestingly, the major effector cell population for this BsAb were polymorphonuclear neutrophils, which proved ineffective in killing malignant B cells with murine, chimeric IgG1, or FcgammaRI- or FcgammaRIII-directed BsAbs against CD20. Experiments with blood from human FcalphaRI/FcgammaRI double-transgenic mice showed corresponding results, allowing the establishment of relevant syngenic animal models in these mice. In conclusion, the combination of myeloid growth factors and an (FcalphaRI x CD20) BsAb may represent a promising approach to improve effector cell recruitment for CD20-directed lymphoma therapy.
CD20抗体可诱导淋巴瘤患者产生临床反应，但个体患者之间存在显著差异。在以全血为效应细胞来源的（51）铬释放试验中，RAJI细胞可被CD20抗体1F5的小鼠/人嵌合IgG1构建体有效杀伤，而ARH - 77细胞对该抗体的杀伤具有抗性。当将全血分离为血浆、单核细胞或粒细胞效应细胞时，在含有补体的血浆存在下，RAJI细胞可被有效杀伤，而成熟B细胞系ARH - 77对补体具有抗性。然而，使用针对IgA髓样受体（CD89；FcalphaRI）和CD20的双特异性抗体（BsAb）时，多种B细胞系可被有效杀伤。FcalphaRI在单核细胞/巨噬细胞、中性粒细胞和嗜酸性粒细胞上表达。由于应用G - CSF或GM - CSF可增加这些效应细胞的数量及其功能活性，在使用这些髓样生长因子治疗的患者血液中，通过（FcalphaRI×CD20）BsAb介导的细胞裂解作用显著增强。有趣的是，该BsAb的主要效应细胞群体是多形核中性粒细胞，而在用针对CD20的鼠源、嵌合IgG1或FcgammaRI - 或FcgammaRIII导向的BsAb杀伤恶性B细胞时，多形核中性粒细胞却无效。用人FcalphaRI/FcgammaRI双转基因小鼠的血液进行的实验显示了相应结果，从而能够在这些小鼠中建立相关的同基因动物模型。总之，髓样生长因子与（FcalphaRI×CD20）BsAb的联合应用可能是一种有前景的方法，可改善针对CD20的淋巴瘤治疗中效应细胞的募集。
