PO.CH01.06 · 化学
一种新型携带双载荷的2+2 IgG样双特异性抗体偶联药物，用于异质性胃肠道癌症的靶向治疗
A novel 2+2 IgG-like bispecific antibody-drug conjugate with dual payloads for targeted therapy of heterogeneous gastrointestinal cancers
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摘要 Abstract
中文摘要
胃肠道（GI）癌症，包括结直肠癌、胃癌和胰腺癌，由于其高发病率、侵袭性进展和显著的瘤内异质性，仍是全球癌症相关死亡的主要原因。这种异质性常导致治疗耐药，并限制了单药疗法的疗效。钙黏蛋白-17（CDH17）和鸟苷酸环化酶C（GUCY2C）是两种有前景的肿瘤相关抗原（TAAs），它们在各种GI癌症中广泛而特异地过表达，使其成为双特异性治疗的理想靶点。双特异性抗体（bsAbs）通过共同靶向两种不同抗原提供了战略优势，可能增强肿瘤选择性、克服异质性并改善治疗结果。在此，我们报告了一种同时靶向CDH17和GUCY2C的新型2+2 IgG样双特异性抗体偶联药物（ADC）的开发，其经工程改造以满足GI癌症治疗中未被满足的需求。该双特异性抗体被构建为2+2 IgG样分子。CDH17结合臂源自一个从免疫羊驼文库中分离的人源化单域抗体（VHH），因其高亲和力和特异性而被选中。GUCY2C结合臂是一种全人源IgG1 kappa抗体，通过对人噬菌体展示文库进行生物淘选而鉴定得到。所得bsAb被位点特异性地偶联到来自杭州DAC的一种专有双载荷连接子-药物系统，该系统由一种强效抗代谢药物和一种拓扑异构酶I抑制剂组成。该bsAb对CDH17和GUCY2C均表现出高亲和力结合（KD值处于低纳摩尔范围），并展现出对表达其中一种或两种抗原的细胞的双特异性结合。该ADC药物还对单抗原和双抗原表达的肿瘤细胞均展现出强效细胞毒性。该ADC令人鼓舞的临床前疗效特征支持其作为晚期GI癌症患者靶向治疗的潜力，提供了一种克服治疗耐药、改善临床结果的新策略。
查看英文原文 English abstract
Gastrointestinal (GI) cancers, including colorectal, gastric, and pancreatic cancers, remain a leading cause of cancer-related mortality globally due to their high incidence, aggressive progression, and profound intratumoral heterogeneity. This heterogeneity often leads to treatment resistance and limits the efficacy of monotherapies. Cadherin-17 (CDH17) and Guanylate Cyclase C (GUCY2C) are two promising tumor-associated antigens (TAAs) that are broadly and specifically overexpressed in various GI cancers, making them ideal targets for dual-specific therapy. Bispecific antibodies (bsAbs) offer a strategic advantage by co-targeting two distinct antigens, potentially enhancing tumor selectivity, overcoming heterogeneity, and improving therapeutic outcomes. Here, we report the development of a novel 2+2 IgG-like bispecific antibody-drug conjugate (ADC) targeting both CDH17 and GUCY2C, engineered to address the unmet needs in GI cancer treatment. The bispecific antibody was constructed as a 2+2 IgG-like molecule. The CDH17-binding arm was derived from a humanized single-domain antibody (VHH) isolated from an immunized alpaca library, selected for high affinity and specificity. The GUCY2C-binding arm was a fully human IgG1 kappa antibody identified through biopanning of a human phage display library. The resulting bsAb was site-specifically conjugated to a proprietary dual-payload linker-drug system from Hangzhou DAC, consisting of a potent antimetabolite drug and a topoisomerase I inhibitor. The bsAb exhibited high-affinity binding to both CDH17 and GUCY2C (KD values in the low nanomolar range) and demonstrated dual-specific binding to cells expressing either or both antigens. This ADC agent also demonstrated potent cytotoxicity against both single and dual antigen-expressing tumor cells. The promising preclinical efficacy profile of this ADC support its potential as a targeted therapy for patients with advanced GI cancers, offering a new strategy to overcome treatment resistance and improve clinical outcomes.
利益披露 Disclosure
W. Zheng, None..
J. Jia, None..
X. Liu, None..
G. Zhao, None..
Y. Chen, None..
X. Zhou, None..
S. Zhao, None..
Q. Yang, None..
R. Y. Zhao, None.