PO.IM01.15 · 免疫学
新型单克隆抗体通过LFA-1/ICAM-1依赖的抗体介导的细胞毒性杀伤淋巴瘤细胞
Novel monoclonal antibody kills lymphoma cells via LFA-1/ICAM-1 dependent, antibody-mediated cellular cytotoxicity
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：弥漫性大B细胞淋巴瘤（DLBCL）是一种侵袭性的非霍奇金淋巴瘤。DLBCL患者接受一线免疫化疗方案，称为R-CHOP。遗憾的是，约40%的接受治疗患者最终复发或无应答。因此，迫切需要设计新的治疗选择。近来，一种新型单克隆抗体（抗体X）已被开发作为潜在的治疗策略。
方法：使用表达CD16（Fc受体）的NK92细胞作为效应细胞，在共培养实验中对抗靶DLBCL细胞系。开发了一种高内涵、高通量药物筛选工具，以测试小分子药物与免疫治疗联合的效果。
结果：我们观察到，抗体X并非通过直接细胞毒性或补体依赖性细胞毒性，而是主要通过抗体依赖性细胞介导的细胞毒性（ADCC）发挥其抗肿瘤作用。为了解抗体X介导杀伤的调控因子，我们利用一种新开发的高内涵、高通量药物筛选工具，评估了1000多种FDA批准化合物对抗体X介导的DLBCL细胞ADCC的影响。我们注意到，BCR-Abl抑制剂通过其对Src激酶的作用差异性地调控抗体X介导的ADCC。淋巴瘤细胞与免疫效应细胞之间的细胞接触也通过阻断LFA-1/ICAM-1免疫突触形成而被破坏。这最终导致淋巴瘤细胞不发生死亡。
结论：总体而言，本研究的发现揭示了抗体X介导的ADCC依赖于Src活性和LFA-1/ICAM-1免疫突触。我们还证明，这种新型高内涵、高通量ADCC平台可用于基于免疫治疗的联合药物筛选和ADCC的机制评估。
[E.K.C.和A.D.J.为本研究的共同通讯作者。]
查看英文原文 English abstract
Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin's lymphoma. DLBCL patients undergo a first line immunochemotherapy regimen, termed R-CHOP. Unfortunately, approximately 40% of treated patients eventually relapse, or are non-responsive. Thus, there is an urgent need to devise new treatment options. Recently, a novel monoclonal antibody (Antibody X) has been developed as a potential therapeutic strategy.
Methods: CD16 (Fc receptor)-expressing NK92 cells were used as effector cells against target DLCBL cell lines in co-culture assays. A high-content, high-throughput drug screening tool was developed to test the effects of small molecule drugs in combination with immunotherapies.
Results: We observed that instead of direct cytotoxicity or complement-dependent cytotoxicity, Antibody X exerted its anti-tumour effect primarily through antibody-dependent cellular cytotoxicity (ADCC). To understand the regulators of Antibody X-mediated killing, we utilised a newly developed high-content, high-throughput drug screening tool to evaluate the effects of over 1000 FDA approved compounds on Antibody X-mediated ADCC of DLBCL cells. We noted that BCR-Abl inhibitors differentially regulated Antibody X-mediated ADCC through their effects on Src kinases. Cellular contact between lymphoma cells and immune effector cells was also disrupted through the blockade of LFA-1/ICAM-1 immunological synapse formation. This ultimately led to an absence of death in lymphoma cells.
Conclusion: Overall, findings from this study revealed that Antibody X-mediated ADCC is dependent on Src activity and LFA-1/ICAM-1 immunological synapses. We also demonstrated that the novel high-content, high-throughput ADCC platform can be used for immunotherapy-based combinatorial drug screens and mechanistic evaluation of ADCC.
[E.K.C. and A.D.J. are co-corresponding authors for this work.]
利益披露 Disclosure
R. Lee, None..
P. W. Jaynes, None..
E. Chow, None.