The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, Maryland 21205, United States.
Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, Maryland 21205, United States.
Mol Pharm. 2020 Sep 8;17(9):3392-3402. doi: 10.1021/acs.molpharmaceut.0c00457. Epub 2020 Aug 17.
Prostate cancer (PC) is a potentially high-risk disease and the most common cancer in American men. It is a leading cause of cancer-related deaths in men in the US, second only to lung and bronchus cancer. Advanced and metastatic PC is initially treated with androgen deprivation therapy (ADT), but nearly all cases eventually progress to castrate-resistant prostate cancer (CRPC). CRPC is incurable in the metastatic stage but can be slowed by some conventional chemotherapeutics and second-generation ADT, such as enzalutamide and abiraterone. Therefore, novel therapeutic strategies are urgently needed. Prostate-specific membrane antigen (PSMA) is overexpressed in almost all aggressive PCs. PSMA is widely used as a target for PC imaging and drug delivery. Anti-PSMA monoclonal antibodies (mAbs) have been developed as bioligands for diagnostic imaging and targeted PC therapy. However, these mAbs are successfully used in PC imaging and only a few have gone beyond phase-I for targeted therapy. The 5D3 mAb is a novel, high-affinity, and fast-internalizing anti-PSMA antibody. Importantly, 5D3 mAb demonstrates a unique pattern of cellular localization to the centrosome after internalization in PSMA(+) PC3-PIP cells. These characteristics make 5D3 mAb an ideal bioligand to deliver tubulin inhibitors, such as mertansine, to the cell centrosome, leading to mitotic arrest and elimination of dividing PC cells. We have successfully developed a 5D3 mAb- and mertansine (DM1)-based antibody-drug conjugate (ADC) and evaluated it for binding affinity, internalization, and cytotoxicity. The therapeutic efficacy of 5D3-DM1 ADC was evaluated in PSMA(+) PC3-PIP and PSMA(-) PC3-Flu mouse models of human PC. This therapeutic study has revealed that this new anti-PSMA ADC can successfully control the growth of PSMA(+) tumors without inducing systemic toxicity.
前列腺癌（PC）是一种潜在的高风险疾病，也是美国男性最常见的癌症。它是美国男性癌症相关死亡的主要原因，仅次于肺癌和支气管癌。晚期和转移性 PC 最初采用雄激素剥夺疗法（ADT）治疗，但几乎所有病例最终都会进展为去势抵抗性前列腺癌（CRPC）。在转移性阶段，CRPC 无法治愈，但可以通过一些传统的化疗药物和第二代 ADT （如恩扎鲁胺和阿比特龙）来减缓其发展。因此，迫切需要新的治疗策略。前列腺特异性膜抗原（PSMA）在几乎所有侵袭性 PC 中均过度表达。PSMA 被广泛用作 PC 成像和药物输送的靶标。抗 PSMA 单克隆抗体（mAb）已被开发为用于诊断成像和靶向 PC 治疗的生物配体。然而，这些 mAb 已成功用于 PC 成像，只有少数 mAb 已超越靶向治疗的 I 期临床试验。5D3 mAb 是一种新型的、高亲和力的、快速内化的抗 PSMA 抗体。重要的是，5D3 mAb 在 PSMA（+）PC3-PIP 细胞内化后显示出独特的中心体细胞定位模式。这些特征使 5D3 mAb 成为将微管抑制剂（如美登素）递送至细胞中心体的理想生物配体，从而导致有丝分裂停滞和分裂 PC 细胞的消除。我们已经成功开发了一种基于 5D3 mAb 和美登素（DM1）的抗体药物偶联物（ADC），并对其结合亲和力、内化和细胞毒性进行了评估。在 PSMA（+）PC3-PIP 和 PSMA（-）PC3-Flu 人 PC 小鼠模型中评估了 5D3-DM1 ADC 的治疗效果。这项治疗研究表明，这种新型抗 PSMA ADC 可以成功控制 PSMA（+）肿瘤的生长，而不会引起全身毒性。
