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Efficiency of T Cell Triggering by Anti-Cd3 Monoclonal Antibodies (Mab) with Potential Usefulness in Bispecific Mab Generation

机译:抗Cd3单克隆抗体(Mab)触发T细胞的效率,在双特异性单克隆抗体的产生中可能具有实用性

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摘要

T cell triggering can be achieved by monoclonal antibodies (mAbs) specific for the CD3/TcR complex. In the presence of appropriate costimulation and/or progression factors, such triggering permits the generation of effector cells for immunotherapy protocols involving the redirection of T cell lysis against tumor cells by mAbs bispecific for anti-CD3/anti-tumor cells (bs-mAbs). Focusing our analysis on the clinically relevant bs-mAb OC/TR, we found that bs-mAbs generated with the same anti tumor specificity, but two other anti-CD3 mAbs, TR66 and OKT3, have the same and a significantly lower lytic potential, respectively, compared with that of OC/TR. To evaluate the relevance of the anti-CD3 component, we examined several anti-CD3 mAbs with respect to binding parameters and the ability to trigger T lymphocytes. Competitive binding assays suggested that all anti-CD3 mAbs recognized the same or overlapping epitopes, although mAbs BMA030 and OC/TR bound with lower avidity than did alpha CD3 (the bivalent anti-CD3 mAb produced by the hybrid hybridoma OC/TR). TR66 and OKT3, as determined by measurement of the affinity constants. In all lymphocyte populations examined, which included resting peripheral blood mononuclear cells (PBMC), activated PBMC and T cell clones, OKT3, BMA033 and OC/TR failed to mobilize Ca2+ without cross-linking, whereas alpha CD3, in both murine and murine-human chimeric versions, TR66 and BMA030, did not require cross-linking. The ability to induce CD3 modulation was associated in part with the induction of Ca2+ fluxes. Despite the differences in the behavior of these mAbs in triggering the events that precede proliferation, all of them ultimately led to expression of the IL-2 receptor and to proliferation in T cells in the presence of accessory cells. Our data suggest that anti-CD3 mAbs that bind more rapidly (strong Ca2+ mobilizers) and more tightly under physiological conditions are good candidates for retargeting T cells in the bs-mAb clinical application.
机译:T细胞触发可通过对CD3 / TcR复合物具有特异性的单克隆抗体(mAb)来实现。在存在适当的共刺激和/或进展因子的情况下,此类触发可产生针对免疫治疗方案的效应细胞,该方案涉及通过针对CD3 /抗肿瘤细胞的双特异性mAb重定向T细胞裂解针对肿瘤细胞的方法(bs-mAb) 。将我们的分析集中在与临床相关的bs-mAb OC / TR上,我们发现产生的bs-mAb具有相同的抗肿瘤特异性,但其他两种抗CD3 mAb TR66和OKT3具有相同的裂解潜能,与OC / TR相比。为了评估抗CD3组分的相关性,我们针对结合参数和触发T淋巴细胞的能力检查了几种抗CD3单抗。竞争性结合试验表明,所有抗CD3 mAb都识别相同或重叠的表位,尽管mAb BMA030和OC / TR的亲和力低于αCD3(由杂交杂交瘤OC / TR产生的二价抗CD3 mAb)。 TR66和OKT3,通过亲和常数的测量确定。在所有检查的淋巴细胞群体中,包括静息的外周血单个核细胞(PBMC),活化的PBMC和T细胞克隆,OKT3,BMA033和OC / TR未能动员Ca2 +而未发生交联,而在鼠和鼠中,αCD3均未交联。人类嵌合体版本TR66和BMA030不需要交联。诱导CD3调节的能力部分与诱导Ca2 +通量有关。尽管这些mAb在触发增殖之前的事件方面的行为有所不同,但所有这些最终都导致IL-2受体表达并在存在辅助细胞的情况下在T细胞中增殖。我们的数据表明,在生理条件下结合更快(强Ca2 +动员)和结合更紧密的抗CD3 mAb是在bs-mAb临床应用中重定位T细胞的良好候选者。

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