Preclinical studies of targeted therapies for CD20-positive B lymphoid malignancies by Ofatumumab conjugated with auristatin
Preclinical studies of targeted therapies for CD20-positive B lymphoid malignancies by Ofatumumab conjugated with auristatin
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Ofatumumab 联合 auristatin 靶向治疗 CD20 阳性 B 淋巴恶性肿瘤的临床前研究
DOI：
10.1007/s10637-013-9995-y
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发表时间：
2014-02-01
影响因子：
3.4
通讯作者：
Chen, Shu Qing
中科院分区：
文献类型：
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作者：
Li, Zhao Hui;Zhang, Qian;Chen, Shu Qing
利用抗体将高效细胞毒性剂递送至相应的抗原过表达的肿瘤细胞是临床验证的治疗策略。奥法木单抗（OFA，商品名Arzerra）是一种完全人源性CD 20特异性抗体，对CD 20阳性B细胞淋巴瘤/慢性淋巴细胞白血病细胞具有活性。为了进一步增强OFA的抗癌作用，通过组织蛋白酶-B-可切割的缬氨酸-瓜氨酸（vc）二肽键将抗CD 20 OFA与高细胞毒性的单甲基奥瑞他汀E（MMAE）缀合以形成OFA-vcMMAE，然后在体外和体内评价OFA-vcMMAE对CD 20阳性B淋巴瘤细胞的抗肿瘤活性。因此，OFA与MMAE的缀合保持了OFA的初始效应子功能活性，如结合亲和力、补体依赖性细胞毒性（CDC）以及抗体依赖性细胞介导的细胞毒性（ADCC）。此外，MMAE的缀合显著提高了OFA对CD 20阳性细胞的细胞毒活性（即，Raji、Daudi和WIL 2-S细胞），但不针对CD 20阴性K562细胞。另一方面，OFA-vcMMAE从CD 20阳性细胞表面被调节，然后通过受体介导的内吞作用进入溶酶体，经历蛋白水解降解并释放活性药物MMAE，通过半胱天冬酶-3样蛋白酶依赖性途径诱导凋亡性细胞死亡。令人惊讶的是，OFA-vcMMAE在体内完全抑制了CD 20阳性Daudi和拉莫斯淋巴瘤异种移植物的生长，并且表现出比未缀合的OFA更大的抗肿瘤活性，这表明抗CD 20抗体的抗肿瘤活性可以通过与MMAE缀合而增强。在不久的将来，这种新的方法可能会被用作CD 20阳性B淋巴系统恶性肿瘤的临床治疗。
Utilization of antibodies to deliver highly potent cytotoxic agents to corresponding antigen-overexpressed tumor cells is a clinically validated therapeutic strategy. Ofatumumab (OFA, trade name Arzerra) is a fully human CD20-specific antibody that is active against CD20-positive B-cell lymphoma/chronic lymphocytic leukemia cells. In order to further enhance the anticancer effect of OFA, anti-CD20 OFA has been conjugated with highly cytotoxic monomethyl auristatin E (MMAE) through a cathepsin-B-cleavable valine-citrulline (vc) dipeptide linkage to form OFA-vcMMAE and the anti-tumor activity of OFA-vcMMAE against CD20-positive B lymphoma cells are then evaluated in vitro and in vivo. As a result, conjugation of OFA with MMAE has kept the initial effector functional activities of OFA such as binding affinity, complement-dependent cytotoxicity (CDC) as well as antibody-dependent cell-mediated cytotoxicity (ADCC). In addition, the conjugation of MMAE significantly improved the cytotoxic activity of OFA against CD20-positive cells (i.e., Raji, Daudi and WIL2-S cells) but not against CD20-negative K562 cells. On the other hand, OFA-vcMMAE was modulated from the CD20-positive cell surface and then entered the lysosomes by receptor-mediated endocytosis, underwent proteolytic degradation and released active drug MMAE to induce apoptotic cell death through a caspase-3-like protease-dependent pathway. Surprisingly, OFA-vcMMAE completely inhibited the growth of CD20-positive Daudi and Ramos lymphoma xenografts in vivo, and exhibited greater anti-tumor activity than unconjugated OFA, suggesting that the anti-tumor activity of anti-CD20 antibody can be enhanced by conjugation with MMAE. In the near future, this new approach might be used as a clinical treatment of CD20-positive B lymphoid malignancies.