PO.ET02.05 · 实验与分子治疗
开发一种新型靶向PSCA的抗体偶联药物，具有高效力和高稳定性，用于前列腺癌治疗
Development of a novel PSCA-targeting antibody-drug conjugate with high potency and stability for prostate cancer therapy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
抗体偶联药物（ADC）能够将高细胞毒性载荷选择性地递送至肿瘤，正在成为前列腺癌治疗中一种新的、有前景的选择。前列腺干细胞抗原（PSCA）是一种细胞表面抗原，在前列腺癌中高度过表达，并在疾病晚期状态下上调，而在正常组织中表达极少，使其成为ADC治疗的理想靶点。在本研究中，我们鉴定并生成了全长人源抗PSCA抗体，其对表达PSCA的癌细胞表现出高结合亲和力和快速内化能力。使用经化学验证的连接子，将多种细胞毒性药物（如单甲基澳瑞他汀E（MMAE）、DM1等）偶联至先导抗人PSCA抗体（A2）。在由此产生的ADC候选物中，A2-MMAE对PSCA阳性的人前列腺癌细胞系表现出最强的、浓度依赖性的细胞毒性，IC₅₀范围为0.18-2.17 nM，而对PSCA阴性细胞则无细胞毒性。疏水相互作用色谱（HIC-HPLC）分析显示药物抗体比（DAR）呈异质分布，平均DAR为4.84。此外，A2-MMAE在小鼠血浆中孵育10天后仍保持较高的总体ADC完整性，表明其具有强健的血浆稳定性。这些发现表明，这种新型抗PSCA ADC（anti-PSCA-VC-PAB-MMAE）以其强大的靶点特异性、高效力和优异的稳定性为特征，有望成为一种更安全、更有效的前列腺癌治疗药物。正在进行的研究将评估其在小鼠模型中的体内抗肿瘤疗效、耐受性、安全性及药代动力学/药效学（PK/PD）特征。
查看英文原文 English abstract
Antibody-drug conjugates (ADCs) enable the selective delivery of highly cytotoxic payloads to tumors and are emerging as new, promising therapeutic options for prostate cancer. Prostate stem cell antigen (PSCA) is a cell-surface antigen that is highly overexpressed in prostate cancer and upregulated in advanced disease states, while minimally expressed in normal tissues, making it an ideal target for ADC therapy. In this study, we identified and generated full-length human anti-PSCA antibodies, exhibiting high binding affinity and rapid internalization into PSCA-expressing cancer cells. Various cytotoxic drugs (e.g., monomethyl auristatin E (MMAE), DM1, etc.) were conjugated to the lead anti-human PSCA antibody (A2) using a chemically validated linker. Among the resulting ADC candidates, A2-MMAE demonstrated the most potent, concentration-dependent cytotoxicity against PSCA-positive human prostate cancer cell lines, with an IC₅₀ range of 0.18-2.17 nM, while exhibiting no cytotoxicity in PSCA-negative cells. Hydrophobic interaction chromatography (HIC-HPLC) analysis revealed a heterogeneous distribution of drug-to-antibody ratios (DARs), with an average DAR of 4.84. Furthermore, A2-MMAE retained a high level of total ADC integrity following 10 days of incubation in mouse plasma, indicating a robust plasma stability. These findings suggest that the novel anti-PSCA ADC (anti-PSCA-VC-PAB-MMAE), characterized by its strong target specificity, high potency, and excellent stability, holds promise as a safer and more effective therapeutic for prostate cancer. Ongoing studies will evaluate its in vivo antitumor efficacy, tolerability, safety, and pharmacokinetic/pharmacodynamic (PK/PD) profiling in mouse models.
利益披露 Disclosure
Y. Cao, None..
E. A. Kono, None..
R. E. Reiter, None.