Genentech Research and Early Development, 1 DNA Way, South San Francisco, CA 94080, USA.
Mol Cancer Ther. 2013 Jul;12(7):1255-65. doi: 10.1158/1535-7163.MCT-12-1173. Epub 2013 Apr 18.
Antibody-drug conjugates (ADC), potent cytotoxic drugs linked to antibodies via chemical linkers, allow specific targeting of drugs to neoplastic cells. We have used this technology to develop the ADC DCDT2980S that targets CD22, an antigen with expression limited to B cells and the vast majority of non-Hodgkin lymphomas (NHL). DCDT2980S consists of a humanized anti-CD22 monoclonal IgG1 antibody with a potent microtubule-disrupting agent, monomethyl auristatin E (MMAE), linked to the reduced cysteines of the antibody via a protease cleavable linker, maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-vc-PAB). We describe the efficacy, safety, and pharmacokinetics of DCDT2980S in animal models to assess its potential as a therapeutic for the treatment of B-cell malignancies. We did not find a strong correlation between in vitro or in vivo efficacy and CD22 surface expression, nor a correlation of sensitivity to free drug and in vitro potency. We show that DCDT2980S was capable of inducing complete tumor regression in xenograft mouse models of NHL and can be more effective than rituximab plus combination chemotherapy at drug exposures that were well tolerated in cynomolgus monkeys. These results suggest that DCDT2980S has an efficacy, safety, and pharmacokinetics profile that support potential treatment of NHL.
抗体药物偶联物（ADC）是通过化学连接子将有效细胞毒性药物与抗体连接起来的药物，使药物能够特异性靶向肿瘤细胞。我们利用这项技术开发了靶向 CD22 的 ADC DCDT2980S，CD22 是一种抗原，仅在 B 细胞和绝大多数非霍奇金淋巴瘤（NHL）中表达。DCDT2980S 由一种人源化抗 CD22 单克隆 IgG1 抗体与一种有效的微管破坏剂单甲基奥瑞他汀 E（MMAE）组成，通过蛋白酶可切割连接子与抗体的还原半胱氨酸连接。该连接子为马来酰亚胺基己酰基-Val-Cit-PAB。我们描述了 DCDT2980S 在动物模型中的疗效、安全性和药代动力学，以评估其作为治疗 B 细胞恶性肿瘤的潜在用途。我们没有发现体外或体内疗效与 CD22 表面表达之间存在很强的相关性，也没有发现游离药物敏感性与体外效力之间存在相关性。我们表明，DCDT2980S 能够诱导 NHL 异种移植小鼠模型中的肿瘤完全消退，并且在在食蟹猴中能够耐受的药物暴露量下，其效果可能优于利妥昔单抗联合化疗。这些结果表明，DCDT2980S 具有疗效、安全性和药代动力学特征，支持其治疗 NHL 的潜力。
