A HER2‐targeted Antibody‐Drug Conjugate, RC48‐ADC, Exerted Promising Antitumor Efficacy and Safety with Intravesical Instillation in Preclinical Models of Bladder Cancer
Abstract More than half of non‐muscle‐invasive bladder cancer (NMIBC) patients eventually relapse even if treated with surgery and BCG without optional bladder‐preserving therapy. This study aims to investigate the antitumor activity and safety of a HER2‐targeted antibody‐drug conjugate, RC48‐ADC, i...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-11-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202302377 |
| _version_ | 1797627724826673152 |
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| author | Xuwei Hong Xu Chen Hongjin Wang Qingchun Xu Kanghua Xiao Yuanfeng Zhang Zepai Chi Yeqing Liu Guangyao Liu Hong Li Jianmin Fang Tianxin Lin Yonghai Zhang |
| author_facet | Xuwei Hong Xu Chen Hongjin Wang Qingchun Xu Kanghua Xiao Yuanfeng Zhang Zepai Chi Yeqing Liu Guangyao Liu Hong Li Jianmin Fang Tianxin Lin Yonghai Zhang |
| author_sort | Xuwei Hong |
| collection | DOAJ |
| description | Abstract More than half of non‐muscle‐invasive bladder cancer (NMIBC) patients eventually relapse even if treated with surgery and BCG without optional bladder‐preserving therapy. This study aims to investigate the antitumor activity and safety of a HER2‐targeted antibody‐drug conjugate, RC48‐ADC, intravesical instillation for NMIBC treatment. In this preclinical study, it is revealed that human epidermal growth factor receptor 2 (HER2) expression scores of 1+, 2+, and 3+ are recorded for 16.7%, 56.2%, and 14.6% of NMIBC cases. The antitumor effect of RC48‐ADC is positively correlated with HER2 expression in bladder cancer (BCa) cell lines and organoid models. Furthermore, RC48‐ADC is revealed to exert its antitumor effect by inducing G2/M arrest and caspase‐dependent apoptosis. In an orthotopic BCa model, tumor growth is significantly inhibited by intravesical instillation of RC48‐ADC versus disitamab, monomethyl auristatin E, epirubicin, or phosphate‐buffered saline control. The potential toxicity of intravesical RC48‐ADC is also assessed by dose escalation in normal nude mice and revealed that administration of RC48‐ADC by intravesical instillation is safe within the range of effective therapeutic doses. Taken together, RC48‐ADC demonstrates promising antitumor effects and safety with intravesical administration in multiple preclinical models. These findings provide a rational for clinical trials of intravesical RC48‐ADC in NMIBC patients. |
| first_indexed | 2024-03-11T10:28:25Z |
| format | Article |
| id | doaj.art-35a03614143e4a388d5485c73af27f30 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-11T10:28:25Z |
| publishDate | 2023-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-35a03614143e4a388d5485c73af27f302023-11-15T05:46:36ZengWileyAdvanced Science2198-38442023-11-011032n/an/a10.1002/advs.202302377A HER2‐targeted Antibody‐Drug Conjugate, RC48‐ADC, Exerted Promising Antitumor Efficacy and Safety with Intravesical Instillation in Preclinical Models of Bladder CancerXuwei Hong0Xu Chen1Hongjin Wang2Qingchun Xu3Kanghua Xiao4Yuanfeng Zhang5Zepai Chi6Yeqing Liu7Guangyao Liu8Hong Li9Jianmin Fang10Tianxin Lin11Yonghai Zhang12Department of Urology Shantou Central Hospital Shantou Guangdong 515031 P. R. ChinaDepartment of Urology Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou Guangdong 510120 P. R. ChinaDepartment of Urology Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou Guangdong 510120 P. R. ChinaDepartment of Urology Shantou Central Hospital Shantou Guangdong 515031 P. R. ChinaDepartment of Urology Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou Guangdong 510120 P. R. ChinaDepartment of Urology Shantou Central Hospital Shantou Guangdong 515031 P. R. ChinaDepartment of Urology Shantou Central Hospital Shantou Guangdong 515031 P. R. ChinaDepartment of Pathology Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou Guangdong 510120 P. R. ChinaSchool of Medicine South China University of Technology Guangzhou Guangdong 510120 P. R. ChinaBioMed Laboratory Guangzhou Jingke Biotech Group Guangzhou Guangdong 510120 P. R. ChinaRemeGen Ltd. Yantai Shandong 264006 P. R. ChinaDepartment of Urology Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou Guangdong 510120 P. R. ChinaDepartment of Urology Shantou Central Hospital Shantou Guangdong 515031 P. R. ChinaAbstract More than half of non‐muscle‐invasive bladder cancer (NMIBC) patients eventually relapse even if treated with surgery and BCG without optional bladder‐preserving therapy. This study aims to investigate the antitumor activity and safety of a HER2‐targeted antibody‐drug conjugate, RC48‐ADC, intravesical instillation for NMIBC treatment. In this preclinical study, it is revealed that human epidermal growth factor receptor 2 (HER2) expression scores of 1+, 2+, and 3+ are recorded for 16.7%, 56.2%, and 14.6% of NMIBC cases. The antitumor effect of RC48‐ADC is positively correlated with HER2 expression in bladder cancer (BCa) cell lines and organoid models. Furthermore, RC48‐ADC is revealed to exert its antitumor effect by inducing G2/M arrest and caspase‐dependent apoptosis. In an orthotopic BCa model, tumor growth is significantly inhibited by intravesical instillation of RC48‐ADC versus disitamab, monomethyl auristatin E, epirubicin, or phosphate‐buffered saline control. The potential toxicity of intravesical RC48‐ADC is also assessed by dose escalation in normal nude mice and revealed that administration of RC48‐ADC by intravesical instillation is safe within the range of effective therapeutic doses. Taken together, RC48‐ADC demonstrates promising antitumor effects and safety with intravesical administration in multiple preclinical models. These findings provide a rational for clinical trials of intravesical RC48‐ADC in NMIBC patients.https://doi.org/10.1002/advs.202302377antitumor activityHER2intravesical instillationnon‐muscle‐invasive bladder cancerRC48‐ADC |
| spellingShingle | Xuwei Hong Xu Chen Hongjin Wang Qingchun Xu Kanghua Xiao Yuanfeng Zhang Zepai Chi Yeqing Liu Guangyao Liu Hong Li Jianmin Fang Tianxin Lin Yonghai Zhang A HER2‐targeted Antibody‐Drug Conjugate, RC48‐ADC, Exerted Promising Antitumor Efficacy and Safety with Intravesical Instillation in Preclinical Models of Bladder Cancer Advanced Science antitumor activity HER2 intravesical instillation non‐muscle‐invasive bladder cancer RC48‐ADC |
| title | A HER2‐targeted Antibody‐Drug Conjugate, RC48‐ADC, Exerted Promising Antitumor Efficacy and Safety with Intravesical Instillation in Preclinical Models of Bladder Cancer |
| title_full | A HER2‐targeted Antibody‐Drug Conjugate, RC48‐ADC, Exerted Promising Antitumor Efficacy and Safety with Intravesical Instillation in Preclinical Models of Bladder Cancer |
| title_fullStr | A HER2‐targeted Antibody‐Drug Conjugate, RC48‐ADC, Exerted Promising Antitumor Efficacy and Safety with Intravesical Instillation in Preclinical Models of Bladder Cancer |
| title_full_unstemmed | A HER2‐targeted Antibody‐Drug Conjugate, RC48‐ADC, Exerted Promising Antitumor Efficacy and Safety with Intravesical Instillation in Preclinical Models of Bladder Cancer |
| title_short | A HER2‐targeted Antibody‐Drug Conjugate, RC48‐ADC, Exerted Promising Antitumor Efficacy and Safety with Intravesical Instillation in Preclinical Models of Bladder Cancer |
| title_sort | her2 targeted antibody drug conjugate rc48 adc exerted promising antitumor efficacy and safety with intravesical instillation in preclinical models of bladder cancer |
| topic | antitumor activity HER2 intravesical instillation non‐muscle‐invasive bladder cancer RC48‐ADC |
| url | https://doi.org/10.1002/advs.202302377 |
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