PDF(Pubmed)
Abstract：
Prostate stem cell antigen (PSCA) is expressed in all stages of prostate cancer, including in advanced androgen-independent tumors and bone metastasis. PSCA may associate with prostate carcinogenesis and lineage plasticity in prostate cancer. PSCA is also a promising theranostic marker for a variety of other solid tumors, including pancreatic adenocarcinoma and renal cell carcinoma. Here, we identified a novel fully human PSCA antibody using phage display methodology. The structure-based affinity maturation yielded a high-affinity binder, F12, which is highly specific and does not bind to 6,000 human membrane proteins based on a membrane proteome array assay. F12 targets PSCA amino acids 63-69 as tested by the peptide scanning microarray, and it cross-reacts with the murine PSCA. IgG1 F12 efficiently internalizes into PSCA-expressing tumor cells. The antimitotic reagent monomethyl auristatin E (MMAE)-conjugated IgG1 F12 (ADC, F12-MMAE) exhibits dose-dependent efficacy and specificity in a human prostate cancer PC-3-PSCA xenograft NSG mouse model. This is a first reported ADC based on a fully human PSCA antibody and MMAE that is characterized in a xenograft murine model, which warrants further optimizations and investigations in additional preclinical tumor models, including prostate and other solid tumors.
摘要：
前列腺干细胞抗原（PSCA）在前列腺癌的各个阶段都有表达，包括晚期雄激素非依赖性肿瘤和骨转移。PSCA可能与前列腺癌的发生和谱系可塑性有关。PSCA也是多种其他实体瘤的有前途的治疗诊断标志物，包括胰腺腺癌和肾细胞癌。这里,我们使用噬菌体展示方法鉴定了一种新型的全人PSCA抗体。基于结构的亲和力成熟产生了高亲和力粘合剂，F12,其是高度特异性的并且基于膜蛋白质组阵列测定不结合6,000个人膜蛋白。通过肽扫描微阵列测试，F12靶向PSCA氨基酸63-69，它与鼠类PSCA发生交叉反应。IgG1F12有效内化到表达PSCA的肿瘤细胞中。抗有丝分裂试剂单甲基奥瑞他汀E（MMAE）-缀合的IgG1F12（ADC，F12-MMAE）在人前列腺癌PC-3-PSCA异种移植NSG小鼠模型中表现出剂量依赖性功效和特异性。这是首次报道的基于全人PSCA抗体和MMAE的ADC，其特征在于异种移植鼠模型。这需要在其他临床前肿瘤模型中进行进一步的优化和研究，包括前列腺和其他实体瘤。
