Research and Early Development, Genentech, South San Francisco, CA 94080, USA.
Leukemia. 2010 Sep;24(9):1566-73. doi: 10.1038/leu.2010.141. Epub 2010 Jul 1.
Antibody-drug conjugates (ADCs) are potent cytotoxic drugs linked to antibodies through chemical linkers, and allow specific targeting of drugs to neoplastic cells. The expression of CD22 is limited to B-cells, and we show that CD22 is expressed on the vast majority of non-Hodgkin's lymphomas (NHLs). An ideal target for an ADC for the treatment of NHL would have limited expression outside the B-cell compartment and be highly effective against NHL. We generated an ADC consisting of a humanized anti-CD22 antibody conjugated to the anti-mitotic agent maytansine with a stable linker (anti-CD22-MCC-DM1). Anti-CD22-MCC-DM1 was broadly effective in in vitro killing assays on NHL B-cell lines. We did not find a strong correlation between in vitro potency and CD22 surface expression, internalization of ADC or sensitivity to free drug. We show that anti-CD22-MCC-DM1 was capable of inducing complete tumor regression in NHL xenograft mouse models. Further, anti-CD22-MCC-DM1 was well tolerated in cynomolgus monkeys and substantially decreased circulating B-cells as well as follicle size and germinal center formation in lymphoid organs. These results suggest that anti-CD22-MCC-DM1 has an efficacy, safety and pharmacodynamic profile that support its use as a treatment for NHL.
抗体药物偶联物 (ADC) 是通过化学连接物与抗体连接的强效细胞毒性药物，使药物能够特异性靶向肿瘤细胞。CD22 的表达仅限于 B 细胞，我们发现 CD22 广泛表达于绝大多数非霍奇金淋巴瘤 (NHL)。对于用于 NHL 治疗的 ADC 来说，理想的靶点是在 B 细胞区室之外的表达有限，并且对 NHL 具有高度有效性。我们生成了一种 ADC，由与人源化抗 CD22 抗体连接的抗有丝分裂剂美登素与稳定的连接子 (抗 CD22-MCC-DM1) 组成。抗 CD22-MCC-DM1 在 NHL B 细胞系的体外杀伤测定中具有广泛的有效性。我们没有发现体外效力与 CD22 表面表达、ADC 内化或对游离药物的敏感性之间存在很强的相关性。我们表明，抗 CD22-MCC-DM1 能够诱导 NHL 异种移植小鼠模型中的完全肿瘤消退。此外，抗 CD22-MCC-DM1 在食蟹猴中耐受性良好，可显著减少循环 B 细胞以及淋巴器官中滤泡大小和生发中心形成。这些结果表明，抗 CD22-MCC-DM1 具有疗效、安全性和药效学特征，支持其用于 NHL 的治疗。
