Potent antitumor activity of the anti-CD19 auristatin antibody drug conjugate hBU12-vcMMAE against rituximab-sensitive and -resistant lymphomas
Potent antitumor activity of the anti-CD19 auristatin antibody drug conjugate hBU12-vcMMAE against rituximab-sensitive and -resistant lymphomas
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DOI：
10.1182/blood-2008-09-179143
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发表时间：
2009-04-30
期刊：
影响因子：
20.3
通讯作者：
Grewal, Iqbal S.
中科院分区：
文献类型：
--
作者：
Gerber, Hans-Peter;Kung-Sutherland, May;Grewal, Iqbal S.
尽管非霍奇金淋巴瘤（NHL）的治疗取得了重大进展，包括使用化疗药物和抗CD 20抗体利妥昔单抗，但大多数患者最终会复发，需要使用非交叉耐药化合物进行补救治疗以进一步改善患者生存率。在此，我们评估了微管去稳定剂单甲基澳瑞他汀E（MMAE）通过蛋白酶敏感性缬氨酸-瓜氨酸（vc）二肽接头与人源化抗CD 19抗体hBU 12偶联的抗肿瘤作用。hBU 12-vcMMAE诱导针对利妥昔单抗敏感性和耐药性NHL细胞系的有效肿瘤细胞杀伤。CD 19可以与CD 21形成异二聚体，并且据报道高水平的CD 21会负面干扰靶向CD 19的治疗剂的活性。然而，我们在用hBU 12-vcMMAE治疗的CD 21（低）和CD 21（高）、利妥昔单抗敏感性和难治性淋巴瘤中观察到相当的内化、细胞内运输和药物释放。此外，在植入这些肿瘤的小鼠中观察到高比率的持久消退，表明利妥昔单抗抗性和CD 21表达水平均不影响hBU 12-vcMMAE的活性。结合，我们的数据表明，hBU 12-vcMMAE可能代表一个有前途的除了利妥昔单抗难治性NHL和其他血液恶性肿瘤，包括急性淋巴细胞白血病的治疗选择。（血。2009; 113：4352-4361）
Despite major advances in the treatment of non-Hodgkin lymphoma (NHL), including the use of chemotherapeutic agents and the anti-CD20 antibody rituximab, the majority of patients eventually relapse, and salvage treatments with non-cross-resistant compounds are needed to further improve patient survival. Here, we evaluated the antitumor effects of the microtubule destabilizing agent monomethyl auristatin E (MMAE) conjugated to the humanized anti-CD19 antibody hBU12 via a protease-sensitive valine-citrulline (vc) dipeptide linker. hBU12-vcMMAE induced potent tumor cell killing against rituximab-sensitive and -resistant NHL cell lines. CD19 can form heterodimers with CD21, and high levels of CD21 were reported to interfere negatively with the activity of CD19-targeted therapeutics. However, we observed comparable internalization, intracellular trafficking, and drug release in CD21(low) and CD21(high), rituximab-sensitive and -refractory lymphomas treated with hBU12-vcMMAE. Furthermore, high rates of durable regressions in mice implanted with these tumors were observed, suggesting that both rituximab resistance and CD21 expression levels do not impact on the activity of hBU12-vcMMAE. Combined, our data suggest that hBU12-vcMMAE may represent a promising addition to the treatment options for rituximab refractory NHL and other hematologic malignancies, including acute lymphoblastic leukemia. (Blood. 2009; 113: 4352-4361)