Koolwijk P, Van de Winkel J G, Otten I, Bast B J
Department of Molecular Biology and Biotechnology, University of Utrecht, The Netherlands.
Immunology. 1992 Feb;75(2):336-42.
In this study, we describe the ability of hybrid mouse monoclonal antibody (mAb) to induce monocyte-mediated cytotoxicity towards human IgA1-coated E (HuIgA1-E), and the effect of mAb binding valency on Fc gamma RI-mediated ADCC. All hybrid monospecific (ms) anti-HuIgA1 and bispecific (bs) anti-HuIgA1/HRP mAb were capable of inducing monocyte-mediated lysis of HuIgA1-E, in spite of differences in mAb densities essential for optimal lysis. The cytotoxicity induced by hybrid mAb which consist of one or more mIgG2a H chains was predominantly mediated via Fc gamma RI, as shown by inhibition studies on monocytes with Fc gamma RI-blocking mAb TB-3 (approximately 80% inhibition). However, partial inhibition of mIgG1-2a and mIgG2a-2b-induced cytotoxicity (20-50%) was observed by using Fc gamma RII-blocking mAb IV.3 or CIKM5. For hybrid mIgG1-1 mAb the opposite was true; the cytotoxicity was predominantly mediated via Fc gamma RII (70-80%) and less via Fc gamma RI (20-30%). Comparing the hybrid ms anti-HuIgA1 mAb-induced cytotoxicity with the cytotoxicity induced by hybrid bs anti-HuIgA1/HRP mAb of the same isotype, we observed a decrease in cytotoxicity towards HuIgA1-E sensitized with univalently bound bs anti-HuIgA1/HRP mAb. This decrease was only found for Fc gamma RI-mediated ADCC (mIgG2a-2a, mIgG1-2a and mIgG2a-2b). This diminished recognition of univalently bound IgG relative to bivalently bound IgG by Fc gamma RI was also observed with U937 effector cells. In conclusion, this work shows that hybrid mAb are able to induce monocyte-mediated cytotoxicity towards E-HuIgA1 and that there appears to be an effect of Ag-IgG binding valency on Fc gamma RI-mediated cytotoxicity.
在本研究中，我们描述了杂交小鼠单克隆抗体（mAb）诱导单核细胞对人IgA1包被的E（HuIgA1-E）产生细胞毒性的能力，以及mAb结合价态对FcγRI介导的抗体依赖的细胞介导的细胞毒性（ADCC）的影响。尽管实现最佳裂解所需的mAb密度存在差异，但所有杂交单特异性（ms）抗HuIgA1和双特异性（bs）抗HuIgA1/HRP mAb均能够诱导单核细胞介导的HuIgA1-E裂解。由一条或多条mIgG2a重链组成的杂交mAb诱导的细胞毒性主要通过FcγRI介导，用FcγRI阻断mAb TB-3处理单核细胞的抑制研究表明（约80%抑制）。然而，使用FcγRII阻断mAb IV.3或CIKM5观察到mIgG1-2a和mIgG2a-2b诱导的细胞毒性有部分抑制（20-50%）。对于杂交mIgG1-1 mAb，情况相反；细胞毒性主要通过FcγRII介导（70-80%），通过FcγRI介导的较少（20-30%）。将杂交ms抗HuIgA1 mAb诱导的细胞毒性与相同亚型的杂交bs抗HuIgA1/HRP mAb诱导的细胞毒性进行比较，我们观察到用单价结合的bs抗HuIgA1/HRP mAb致敏的HuIgA1-E的细胞毒性降低。这种降低仅在FcγRI介导的ADCC（mIgG2a-2a、mIgG1-2a和mIgG2a-2b）中发现。在用U937效应细胞进行的实验中也观察到，相对于二价结合的IgG，FcγRI对单价结合的IgG的识别减少。总之，这项工作表明杂交mAb能够诱导单核细胞对E-HuIgA1产生细胞毒性，并且Ag-IgG结合价态似乎对FcγRI介导的细胞毒性有影响。
