2. Academic Validation
  3. Overcoming multidrug resistance in gastrointestinal cancers with a CDH17-targeted ADC conjugated to a DNA topoisomerase inhibitor

Overcoming multidrug resistance in gastrointestinal cancers with a CDH17-targeted ADC conjugated to a DNA topoisomerase inhibitor

  • Cell Rep Med. 2025 Jul 15;6(7):102213. doi: 10.1016/j.xcrm.2025.102213.
Rui Wang 1,  Peng Fang 1,  Xi Chen 2,  Jiali Ji 1,  Dongan Yu 3,  Fei Mei 3,  Zhenzhen Wang 1,  Wei Zhou 1,  Wenjing Peng 1,  Rongjuan Wang 4,  Jian Wang 1,  Cuicui Guo 1,  Hai Wu 1,  Datao Liu 5,  Xiaoding Tan 6,  Xun Gui 7
Affiliations

Affiliations

  • 1 Mabwell (Shanghai) Bioscience Co., Ltd., Shanghai 201210, China.
  • 2 Mabwell (Shanghai) Bioscience Co., Ltd., Shanghai 201210, China; National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China.
  • 3 Mabwell (Shanghai) Bioscience Co., Ltd., Shanghai 201210, China; Jiangsu Mabwell Health Pharmaceutical R&D Co., Ltd., Taizhou 225300, China.
  • 4 Mabwell (Shanghai) Bioscience Co., Ltd., Shanghai 201210, China; Beijing Kohnoor Science & Technology Co., Ltd., Beijing 102206, China.
  • 5 Mabwell (Shanghai) Bioscience Co., Ltd., Shanghai 201210, China; National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, China. Electronic address: datao.liu@mabwell.com.
  • 6 Mabwell (Shanghai) Bioscience Co., Ltd., Shanghai 201210, China; Jiangsu Mabwell Health Pharmaceutical R&D Co., Ltd., Taizhou 225300, China. Electronic address: xiaoding.tan@mabwell.com.
  • 7 Mabwell (Shanghai) Bioscience Co., Ltd., Shanghai 201210, China. Electronic address: xun.gui@mabwell.com.
PMID: 40602407 DOI: 10.1016/j.xcrm.2025.102213
Abstract

Cadherin 17 (CDH17) has emerged as a promising target for gastrointestinal (GI) cancers, which are often complicated by multidrug resistance (MDR) and recurrence. In this study, we developed 7MW4911, a CDH17-targeted antibody-drug conjugate (ADC) that incorporates a Topoisomerase Inhibitor MF-6 (Topi MF-6) payload linked via a Cleavable Linker, designed specifically to address MDR in GI cancers. 7MW4911 exhibited high specificity for CDH17-expressing Cancer cells and potent cytotoxicity in vitro. In preclinical models, including patient-derived xenografts (PDXs) with distinct mutations, 7MW4911 achieved tumor growth inhibition ranging from 71% to 99%. Remarkably, 7MW4911 outperformed monomethyl Auristatin E (MMAE)-based and Deruxtecan (DXd)-based ADCs in MDR models, highlighting its effectiveness against drug-resistant Cancer phenotypes. Additionally, 7MW4911 showed favorable pharmacokinetics and a highest non-severely toxic dose (HNSTD) exceeding 20 mg/kg in cynomolgus monkeys, underscoring its promising safety profile. Together, these findings position 7MW4911 as a promising ADC candidate capable of enhancing therapeutic outcomes in GI cancers.

Keywords

ADC; CDH17; colorectal cancer; gastrointestinal cancers; multidrug resistance.

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