Po Yee Wong, Lin He, Kronos Chow, Kwan Wa Wong, Chui Yee O, Dennis Wong, J. M. Luk, Pui-Chi Lo, K. F. Wong
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引用次数: 0
Abstract
Antibody-drug conjugates (ADC) for oncology indications have been developed, however, only few of them are approved for the treatment of gastrointestinal (GI) cancers, which represent as a huge unmet medical need. As such, we developed a novel ADC of which monomethyl auristatin E (MMAE), an antimitotic agent, was conjugated to a cadherin-17 (CDH17)-targeting monoclonal antibody via protease-cleavable peptide valine-citrulline linker. CDH17 is highly restricted to the intestinal adherent junctions which is not accessible in healthy individuals. In contrast, it is overexpressed and becomes reachable in over half of the gastric and pancreatic cancer patients and in more than 95% of patients with colorectal cancer, making it a perfect target for ADC. Our ADC is designed to deliver MMAE specifically to CDH17-expressing tumors to exert the cytotoxic effect of MMAE on cancer cell, mitigating the undesired off-target cytotoxicity. LC/MS analysis revealed that MMAE was conjugated in a drug-to-antibody ratio of 4 with a yield of higher than 75%. ELISA showed that the binding of naked antibody and ADC to CDH17 was comparable (EC50, 0.17 nM & 0.3 nM, respectively), indicating the conjugation process did not affect antigen binding. This ADC also bound to different CDH17-expressing cell lines, including pancreatic AsPC1 and gastric AGS (EC50, 2.1 nM & 1.53 nM, respectively). By labelling the ADC with pH-sensitive fluorescent indicator, we illustrated that ADC internalization only occurred in CDH17+ but not CDH17- cells, suggesting the high specificity of the ADC. Similarly, the ADC showed selective killing on CDH17+ cells (EC50, 0.02-0.5 nM), and the data together proposed a positive correlation between ADC internalization level and its cytotoxicity (R2 = 0.4307). This supported the specificity and safety of the ADC in killing CDH17+ cancer cells only without affecting normal cells. Furthermore, a preliminary in-vivo study on subcutaneous AsPC1 xenograft model demonstrated that the ADC significantly suppressed tumor growth without causing any changes in body weight. Our ADC would potentially be a “First-in-class” ADC for the treatment of GI cancers with minimal adverse systemic toxicity. Further pharmacokinetics, safety, and other IND-enabling studies are underway.
Citation Format: Po Yee Wong, Lin He, Kronos Chow, Kwan Wa Wong, Chui Yee O, Dennis Wong, John Moon Luk, Pui-Chi Lo, Kwong Fai Wong. Novel CDH17-targeting antibody-drug conjugate exhibits anti-tumor efficacy in preclinical models of gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3131.
期刊介绍:
Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research.
With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445.
Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.