Ma Dangshe, Hopf Christine E, Malewicz Andrew D, Donovan Gerald P, Senter Peter D, Goeckeler William F, Maddon Paul J, Olson William C
PSMA Development Co. LLC, Tarrytown, New York, USA.
Clin Cancer Res. 2006 Apr 15;12(8):2591-6. doi: 10.1158/1078-0432.CCR-05-2107.
Prostate-specific membrane antigen (PSMA) is the prototypic cell-surface marker of prostate cancer and provides an attractive target for monoclonal antibody (mAb) targeted therapies. In this study, a novel antibody-drug conjugate (ADC) was generated by linking a fully human PSMA mAb to monomethylauristatin E (MMAE), a potent inhibitor of tubulin polymerization. The PSMA ADC was evaluated for antitumor activity in vitro and in a mouse xenograft model of androgen-independent human prostate cancer. The PSMA ADC eliminated PSMA-expressing cells with picomolar potency and >700-fold selectivity in culture. When used to treat mice with established human C4-2 tumors, the PSMA ADC significantly improved median survival 9-fold relative to vehicle or isotype-matched ADC (P = 0.0018) without toxicity. Treatment effects were also manifest as significant (P = 0.0068) reduction in serum levels of prostate-specific antigen (PSA). Importantly, 40% of treated animals had no detectable tumor or measurable PSA at day 500 and could be considered cured. The findings support development of PSMA antibody-auristatin conjugates for therapy of prostate cancer.
前列腺特异性膜抗原（PSMA）是前列腺癌的典型细胞表面标志物，为单克隆抗体（mAb）靶向治疗提供了一个有吸引力的靶点。在本研究中，通过将一种全人源PSMA单克隆抗体与单甲基澳瑞他汀E（MMAE，一种微管蛋白聚合的强效抑制剂）连接，生成了一种新型抗体药物偶联物（ADC）。对PSMA ADC在体外以及雄激素非依赖性人前列腺癌小鼠异种移植模型中的抗肿瘤活性进行了评估。PSMA ADC在培养物中以皮摩尔效力和>700倍的选择性消除表达PSMA的细胞。当用于治疗患有已建立的人C4-2肿瘤的小鼠时，PSMA ADC相对于赋形剂或同型匹配的ADC显著提高了9倍的中位生存期（P = 0.0018），且无毒性。治疗效果还表现为前列腺特异性抗原（PSA）血清水平显著降低（P = 0.0068）。重要的是，40%接受治疗的动物在第500天时没有可检测到的肿瘤或可测量的PSA，可被视为治愈。这些发现支持开发PSMA抗体-澳瑞他汀偶联物用于前列腺癌治疗。
