PO.ET02.04 · 实验与分子治疗
BCG037，一种首创的抗人ALPP/ALPG治疗性ADC，在胰腺癌和胃癌PDX模型中抑制肿瘤生长
BCG037, a first-in-class anti-human ALPP/ALPG therapeutic ADC that inhibits tumor growth in pancreatic cancer and gastric cancer PDX models
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摘要 Abstract
中文摘要
胎盘型（ALPP）和生殖细胞型（ALPG）碱性磷酸酶共享98%的序列同源性，是具有高度受限表达特征的肿瘤相关抗原。虽然它们在正常成人组织中大多缺失，但在广泛的恶性肿瘤谱中频繁过表达，包括胰腺癌、胃癌、卵巢癌和肺癌。ALPP/ALPG水平升高与胃癌和卵巢癌的不良预后相关，使其成为基于抗体的疗法的引人注目的靶点。在此，我们报告BCG037的开发，这是一种首创的、全人源IgG1抗体偶联药物（ADC），靶向ALPP/ALPG。该抗体源自RenMab™人源化小鼠，并偶联强效的拓扑异构酶I（Top1）抑制剂载荷，实现了约8的高药物抗体比（DAR）。BCG037对人和食蟹猴的ALPP/ALPG均表现出高亲和力（纳摩尔级）和交叉反应性，而与其他ALP家族成员（ALPL、ALPI）无交叉反应。值得注意的是，BCG037的抗体组分与SGN-ALPV中使用的类似物相比，对肿瘤细胞展现出更优的结合亲和力。在体内，BCG037治疗在胰腺癌和胃癌患者来源异种移植（PDX）模型中均带来了显著且更优的肿瘤生长抑制，优于基准ADC SGN-ALPV-MMAE，且在小鼠中未观察到治疗相关毒性或体重下降。总之，这些数据验证了ALPP/ALPG作为有前景的治疗靶点，并将BCG037定位为一种高度新颖且强效的临床候选药物，用于治疗ALPP/ALPG阳性恶性肿瘤，包括治疗选择有限的难治性癌症。
查看英文原文 English abstract
Placental (ALPP) and germ cell (ALPG) alkaline phosphatases, sharing 98% sequence homology, are tumor-associated antigens with a highly restricted expression profile. While largely absent in normal adult tissues, they are frequently overexpressed across a wide spectrum of malignancies, including pancreatic, gastric, ovarian, and lung cancers. Elevated ALPP/ALPG levels correlate with poor prognosis in gastric and ovarian cancers, making them compelling targets for antibody-based therapies. Here, we report the development of BCG037, a first-in-class, fully human IgG1 antibody-drug conjugate (ADC) targeting ALPP/ALPG. The antibody was generated from RenMab™ humanized mice and conjugated with the potent topoisomerase I (Top1) inhibitor payload, achieving a high drug-to-antibody ratio (DAR) of ~8. BCG037 exhibits high affinity (nanomolar range) and cross-reactivity to both human and cynomolgus monkey ALPP/ALPG, with no cross-reactivity to other ALP family members (ALPL, ALPI). Notably, the antibody component of BCG037 demonstrates superior binding affinity to tumor cells compared to the analog used in SGN-ALPV. In vivo , BCG037 treatment led to significant and superior tumor growth inhibition in both pancreatic and gastric cancer patient-derived xenograft (PDX) models, outperforming the benchmark ADC, SGN-ALPV-MMAE, and no treatment-related toxicity or weight loss was observed in mice. Collectively, these data validate ALPP/ALPG as promising therapeutic targets and position BCG037 as a highly novel and potent clinical candidate for treating ALPP/ALPG-positive malignancies, including refractory cancers with limited treatment options.
利益披露 Disclosure
Y. Xie, None..
P. Li, None..
Y. Zhu, None..
Y. Guo, None.