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

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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 ( IF 14.3 ) Pub Date : 2023-10-12 , DOI: 10.1002/advs.202302377
Xuwei Hong _{1,

2,

3} , Xu Chen _{2,

3} , Hongjin Wang _{2,

3} , Qingchun Xu ₁ , Kanghua Xiao _{2,

3} , Yuanfeng Zhang ₁ , Zepai Chi ₁ , Yeqing Liu ₄ , Guangyao Liu ₅ , Hong Li ₆ , Jianmin Fang _{7,

8} , Tianxin Lin _{2,

3,

9} , Yonghai Zhang ₁

Affiliation

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.

中文翻译：

HER2 靶向抗体-药物偶联物 RC48-ADC 在膀胱癌临床前模型中通过膀胱内滴注发挥了有希望的抗肿瘤疗效和安全性

超过一半的非肌层浸润性膀胱癌（NMIBC）患者即使接受手术和 BCG 治疗而没有选择保留膀胱治疗，最终也会复发。本研究旨在探讨 HER2 靶向抗体-药物偶联物 RC48-ADC 膀胱内滴注用于 NMIBC 治疗的抗肿瘤活性和安全性。在这项临床前研究中，发现 16.7%、56.2% 和 14.6% 的 NMIBC 病例的人表皮生长因子受体 2 （HER2）表达评分为 1+、2+ 和 3+。RC48-ADC 的抗肿瘤作用与膀胱癌（BCa）细胞系和类器官模型中的 HER2 表达呈正相关。此外，RC48-ADC 通过诱导 G2/M 阻滞和 caspase 依赖性细胞凋亡来发挥其抗肿瘤作用。在原位 BCa 模型中，膀胱内滴注 RC48-ADC 与 disitamab、单甲基 auristatin E、表柔比星或磷酸盐缓冲盐水对照相比，RC48-ADC 的膀胱内滴注可显著抑制肿瘤生长。还通过在正常裸鼠中剂量递增来评估膀胱内 RC48-ADC 的潜在毒性，并揭示在有效治疗剂量范围内通过膀胱内滴注施用 RC48-ADC 是安全的。综上所述，RC48-ADC 在多个临床前模型中膀胱内给药显示出有希望的抗肿瘤效果和安全性。这些发现为 NMIBC 患者膀胱内 RC48-ADC 的临床试验提供了依据。

更新日期：2023-10-12

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