A High-Affinity Antibody-Drug Conjugates Actuximab-MMAE for Potent and Selective Targeting of CEACAM5-Positive Tumors

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-03-29 DOI:10.1016/j.canlet.2025.217685

Yuqi Hu , Xin Du , Jiayu Yuan , Xizhao Gong , Yue Zhu , Hongde Li , Xiaorong Lin , Fang Zheng , Yuliang Ran , Zhenkun Na , Hai Hu

{"title":"A High-Affinity Antibody-Drug Conjugates Actuximab-MMAE for Potent and Selective Targeting of CEACAM5-Positive Tumors","authors":"Yuqi Hu , Xin Du , Jiayu Yuan , Xizhao Gong , Yue Zhu , Hongde Li , Xiaorong Lin , Fang Zheng , Yuliang Ran , Zhenkun Na , Hai Hu","doi":"10.1016/j.canlet.2025.217685","DOIUrl":null,"url":null,"abstract":"<div><div>Antibody-drug conjugates (ADCs) represent a promising class of anti-cancer therapy with an increasingly critical role in treating various tumors. They broaden the range of therapeutic targets, enabling the consideration of tumor-associated proteins that are overexpressed but lack well-defined mechanisms. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a clinically relevant screening marker due to its tumor-specific overexpression, making it an attractive target for ADC development. However, the therapeutic potential of earlier anti-CEACAM5 ADCs has been limited by side effects and suboptimal drug-to-antibody ratios (DARs), restricting their clinical utility. In this study, we developed a novel anti-CEACAM5 ADC (named Actuximab-MMAE), characterized by high affinity, an optimized DAR, and potent tumor-selective cytotoxicity. Actuximab-MMAE demonstrated rapid and effective elimination of CEACAM5-positive tumors <em>in vivo</em> at low doses, while maintaining a favorable safety profile. These findings highlight Actuximab-MMAE as a promising therapeutic option for CEACAM5-overexpressing tumors, offering a new therapeutic method for targeted cancer therapy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"620 ","pages":"Article 217685"},"PeriodicalIF":9.1000,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0304383525002514","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Antibody-drug conjugates (ADCs) represent a promising class of anti-cancer therapy with an increasingly critical role in treating various tumors. They broaden the range of therapeutic targets, enabling the consideration of tumor-associated proteins that are overexpressed but lack well-defined mechanisms. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a clinically relevant screening marker due to its tumor-specific overexpression, making it an attractive target for ADC development. However, the therapeutic potential of earlier anti-CEACAM5 ADCs has been limited by side effects and suboptimal drug-to-antibody ratios (DARs), restricting their clinical utility. In this study, we developed a novel anti-CEACAM5 ADC (named Actuximab-MMAE), characterized by high affinity, an optimized DAR, and potent tumor-selective cytotoxicity. Actuximab-MMAE demonstrated rapid and effective elimination of CEACAM5-positive tumors in vivo at low doses, while maintaining a favorable safety profile. These findings highlight Actuximab-MMAE as a promising therapeutic option for CEACAM5-overexpressing tumors, offering a new therapeutic method for targeted cancer therapy.

查看原文本刊更多论文

一种高亲和力抗体-药物偶联Actuximab-MMAE有效和选择性靶向ceacam5阳性肿瘤。

抗体-药物偶联物（adc）是一类很有前途的抗癌疗法，在治疗各种肿瘤方面发挥着越来越重要的作用。它们扩大了治疗靶点的范围，使人们能够考虑过度表达但缺乏明确机制的肿瘤相关蛋白。癌胚抗原相关细胞粘附分子5 （CEACAM5）因其肿瘤特异性过表达而成为临床相关的筛选标志物，使其成为ADC发展的一个有吸引力的靶点。然而，早期抗ceacam5 adc的治疗潜力受到副作用和次优药抗体比（dar）的限制，限制了它们的临床应用。在这项研究中，我们开发了一种新的抗ceacam5 ADC（命名为Actuximab-MMAE），其特点是高亲和力，优化的DAR和强大的肿瘤选择性细胞毒性。Actuximab-MMAE在体内低剂量快速有效地消除ceacam5阳性肿瘤，同时保持良好的安全性。这些发现突出了Actuximab-MMAE作为ceacam5过表达肿瘤的有希望的治疗选择，为靶向癌症治疗提供了一种新的治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.