Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan.
Mol Biol Rep. 2022 Jun;49(6):4421-4433. doi: 10.1007/s11033-022-07280-w. Epub 2022 Feb 26.
Obinutuzumab, a Type II anti-CD20 antibody, is used to treat follicular lymphoma. A major mode of action of obinutuzumab is antibody-dependent cellular cytotoxicity (ADCC). Knowledge of the mechanisms of resistance to obinutuzumab is important for the development of next-line strategies to follow obinutuzumab-containing therapy, including obinutuzumab retreatment. Unfortunately, the mechanisms by which tumor cells acquire resistance to ADCC are still poorly understood. To address this, we examined the mechanisms of resistance to obinutuzumab-induced ADCC and the combination efficacy of obinutuzumab and clinically available agents in the established resistant cells.
We established cells resistant to obinutuzumab-induced ADCC using the non-Hodgkin lymphoma cell line RL and examined their mechanisms of resistance and the combination efficacy of obinutuzumab and clinically available agents. Comprehensive analysis by RNA sequencing of resistance mechanisms revealed that abnormal Fas signaling decreased sensitivity to ADCC in resistant clones. Combination treatment with prednisolone, a component of CHOP and CVP, was found to enhance ADCC sensitivity of RL cells and resistant clones and to significantly suppress tumor growth in xenograft models. Treatment with prednisolone upregulated expression of CD20 and an apoptosis-inducing protein BIM, which might augment perforin/granzyme B-mediated cell death. Furthermore, pretreatment of the effector cells with bendamustine enhanced ADCC activity, and treatment with obinutuzumab plus bendamustine showed significant antitumor efficacy in xenograft models. It was speculated that bendamustine upregulates ADCC activity by potentiating granules-mediated cell killing.
Our study revealed a novel mechanism underlying obinutuzumab-induced ADCC resistance and indicated that ADCC resistance could be overcome by combining obinutuzumab with prednisolone or bendamustine. This study provides a scientific rationale for obinutuzumab-retreatment in combination with clinically available chemotherapeutic agents for obinutuzumab resistant follicular lymphoma.
奥滨尤妥珠单抗是一种用于治疗滤泡性淋巴瘤的 II 型抗 CD20 抗体。奥滨尤妥珠单抗的主要作用机制之一是抗体依赖性细胞毒性（ADCC）。了解奥滨尤妥珠单抗耐药的机制对于开发奥滨尤妥珠单抗治疗后序贯策略非常重要，包括奥滨尤妥珠单抗的再治疗。不幸的是，肿瘤细胞获得 ADCC 耐药的机制仍知之甚少。为了解决这个问题，我们研究了奥滨尤妥珠单抗诱导的 ADCC 耐药的机制，以及奥滨尤妥珠单抗与临床可用药物联合在已建立的耐药细胞中的疗效。
我们使用非霍奇金淋巴瘤细胞系 RL 建立了对奥滨尤妥珠单抗诱导的 ADCC 耐药的细胞，并研究了它们的耐药机制以及奥滨尤妥珠单抗与临床可用药物的联合疗效。通过 RNA 测序对耐药机制进行全面分析，发现异常 Fas 信号降低了耐药克隆对 ADCC 的敏感性。我们发现，联合使用地塞米松（CHOP 和 CVP 的组成部分）可增强 RL 细胞和耐药克隆对 ADCC 的敏感性，并显著抑制异种移植模型中的肿瘤生长。地塞米松治疗上调了 CD20 的表达和一种诱导细胞凋亡的蛋白 BIM，这可能增强了穿孔素/颗粒酶 B 介导的细胞死亡。此外，用苯达莫司汀预处理效应细胞可增强 ADCC 活性，奥滨尤妥珠单抗联合苯达莫司汀治疗在异种移植模型中显示出显著的抗肿瘤疗效。据推测，苯达莫司汀通过增强颗粒介导的细胞杀伤来上调 ADCC 活性。
我们的研究揭示了奥滨尤妥珠单抗诱导的 ADCC 耐药的一种新机制，并表明奥滨尤妥珠单抗耐药可以通过与地塞米松或苯达莫司汀联合来克服。这项研究为奥滨尤妥珠单抗耐药滤泡性淋巴瘤的奥滨尤妥珠单抗再治疗联合临床可用化疗药物提供了科学依据。
