PO.ET02.01 · 实验与分子治疗

NW024-1，一种携带拓扑异构酶 1 抑制剂载荷的新型 ALPP/ALPPL2 靶向抗体药物偶联物，展现出强效抗肿瘤疗效

NW024-1, a novel ALPP/ALPPL2-targeting antibody drug conjugate with a topoisomerase 1 inhibitor payload, demonstrates potent antitumor efficacy

编号 1697 展板 26 时间 4/20 09:00–12:00 区域 Section 12 主讲 Zhijian Li, MD

分会场 Antibody-Drug Conjugates and Linker Engineering 1

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作者与单位 Authors & Affiliations

Juanjuan Li¹, Wenting Luo¹, Li Liu¹, Yiran Wu¹, Gang Liu¹, Changcheng Li¹, Yaolan Dai¹, Jiabao Liu¹, Zhijian Li², Lixia Wang¹, Dan Wang¹, Dan Mi¹, Jiaoyi Zhong¹, Bin Liu¹, Desi Pan¹, Zhigang Guo¹

¹Chengdu Chipscreen NewWay Biosciences Co., Ltd., Chengdu, Sichuan, China,²Chipscreen Biosciences (United States) Ltd., Somerset, NJ

摘要 Abstract

中文摘要

背景：胎盘碱性磷酸酶 ALPP 和 ALPPL2 是高度同源（97%）的膜结合蛋白，参与胎儿发育。它们在多种肿瘤细胞中高表达，包括卵巢癌（70%）、子宫内膜癌（41%）、肺癌（NSCLC，25%）和胃癌（25%），但在正常组织中的表达水平有限，使其成为开发抗体药物偶联物（ADC）的理想靶点。在此，我们开发了一种 ALPP/ALPPL2 靶向 ADC NW024-1，它由一种人源化 IgG1 抗 ALPP/ALPPL2 抗体经亲水性连接子偶联至拓扑异构酶 1 抑制剂载荷（TOP1i）构成，旨在将细胞毒性药物选择性递送至表达 ALPP/ALPPL2 的细胞。NW024-1 经体外和体内测试以评估其治疗潜力。方法：对一个 ALPP/ALPPL2 结合克隆文库进行细胞结合、内化和亲和力筛选。人源化抗体采用可切割连接子以 DAR8 偶联至 TOP1i 载荷。在胃癌小鼠异种移植模型（NCI-N87）中评估 NW024-1 的体内疗效，以单剂量 3 mg/kg 和 10 mg/kg 给药评估抗肿瘤活性。结果：该抗体与人 ALPP/ALPPL2 低表达细胞表现出强结合（EC50 = 1.32 nM），但不与人 ALPI/ALPL 高表达细胞结合。在体外，它展现出向 ALPP/ALPPL2 阳性细胞的强健内化能力，以及对 ALPP（KD = 1.32 nM）和 ALPPL2（KD = 0.85 nM）的低纳摩尔亲和力。NW024-1 表现出 ALPP/ALPPL2 依赖性的细胞杀伤。在体内，NW024-1 以单剂量 3 和 10 mg/kg 实现了近乎完全的肿瘤消退（TGI > 95%），并且从体重来看在小鼠中耐受性良好。结论：NW024-1 是一种新型 ADC，展现出良好的特征和强效抗肿瘤疗效。这些发现凸显了其对 ALPP 表达肿瘤的治疗潜力，并支持其进一步推进至临床研究。

查看英文原文 English abstract

Background: Placental alkaline phosphatases, ALPP and ALPPL2, are highly homologous (97%) membrane-bound proteins involved in fetal development. They are highly expressed in a variety of tumor cells including ovarian (70%), endometrial (41%), lung (NSCLC, 25%) and gastric (25%), but have limited expression levels in normal tissues, making them ideal targets for the development of antibody-drug conjugates (ADCs). Here, an ALPP/ALPPL2-targeting ADC NW024-1 was developed, consisting of a humanized IgG1 anti-ALPP/ALPPL2 antibody conjugated via a hydrophilic linker to a topoisomerase 1 inhibitor payload (TOP1i), designed to selectively deliver the cytotoxic agent to ALPP/ALPPL2-expressing cells. NW024-1 was tested in vitro and in vivo to evaluate its therapeutic potential. Methods: A library of ALPP/ALPPL2-binding clones was screened for cell binding, internalization and affinity. The humanized antibody was conjugated to the TOP1i payload with DAR8 using a cleavable linker. The in vivo efficacy of NW024-1 was evaluated in a mouse xenograft model of gastric cancer (NCI-N87), administered with a single dose of 3 mg/kg and 10 mg/kg to evaluate anti-tumor activity. Results: The antibody showed strong binding to human ALPP/ALPPL2 (EC50 = 1.32 nM) low expressing cells, but no binding to human ALPI /ALPL high expressing cells. In vitro, it displayed robust internalization into ALPP/ALPPL2 positive cells and low nanomolar affinity to ALPP (KD = 1.32 nM) and ALPPL2 (KD = 0.85 nM). NW024-1 showed ALPP/ALPPL2-dependent cell killing. In vivo, NW024-1 achieved near-complete tumor regression (TGI > 95%) at 3 and 10 mg/kg for single dose, and was well tolerated in mice as indicated by body weight. Conclusions: NW024-1 is a novel ADC exhibiting a favorable profile and potent antitumor efficacy. These findings highlight its promising therapeutic potential for ALPP-expressing tumors and support its further advancement into clinical investigation.

利益披露 Disclosure

J. Li, None.. W. Luo, None.. L. Liu, None.. Y. Wu, None.. G. Liu, None.. C. Li, None.. Y. Dai, None.. J. Liu, None.. Z. Li, None.. L. Wang, None.. D. Wang, None.. D. Mi, None.. J. Zhong, None.. B. Liu, None.. D. Pan, None.. Z. Guo, None.

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