PO.ET02.02 · 实验与分子治疗
BCG039（一种Nectin-4×TROP2双特异性ADC）在尿路上皮癌及其他实体瘤模型中的临床前研究
Preclinical study of BCG039, a Nectin-4×TROP2 bispecific ADC, in urothelial carcinoma and other solid tumor models
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：尿路上皮癌（UC）每年在全球影响超过60万患者，且发病率在过去十年中不断上升。转移性尿路上皮癌（mUC）预后不良，5年生存率估计低至10-15%。Nectin-4在mUC中高表达。它是mUC的临床验证靶点，enfortumab vedotin（EV）与pembrolizumab联合方案是新确立的一线转移性和局部晚期UC的标准治疗（SOC）。TROP2在UC中也高表达，sacituzumab govitecan（SG）已在后线mUC中显示出治疗活性。Nectin-4xTROP2双特异性ADC旨在靶向mUC中这两个临床验证靶点，以进一步提高疗效并降低毒性。
方法：使用Biocytogen的RenLite®转基因小鼠制备了针对Nectin-4和TROP2的全人源抗体。我们基于内化活性选择双特异性抗体的臂，以1+1形式构建和评估双特异性抗体。双特异性抗体分别偶联至DAR为4的vcMMAE和DAR为4的Biocytogen专有连接子-载荷BLD1102。BLD1102由一种新型TOP1抑制剂载荷和一种高度亲水的酶可裂解连接子组成。所得ADC连同相关基准ADC在小鼠CDX和PDX肿瘤模型中测试抗肿瘤活性。
结果：我们基于内化活性选择臂，nectin-4臂和TROP2臂在1+1双特异性抗体形式下相较于各自的单价亲本臂表现出增强的内化能力，提示两臂之间存在协同相互作用。与该体外观察结果一致，vcMMAE偶联的双特异性ADC（bsADC）在小鼠CDX/PDX模型中相较于单价亲本ADC表现出显著增强的抗肿瘤活性。BLD1102偶联的bsADC——BCG039，也展现出优于基准抗nectin-4和某些基准抗TROP2 ADC的肿瘤生长抑制。该双特异性抗体具有优异的可开发性，目前正处于CMC开发阶段。
结论：BCG039，一种靶向Nectin-4和TROP2的bsADC，在小鼠中展现出优于单靶向亲本ADC和相关基准ADC的抗肿瘤疗效。两臂的协同相互作用也可能有助于降低针对mUC中这些靶点的单靶向ADC所观察到的毒性。
查看英文原文 English abstract
Background: Urothelial carcinoma (UC) affects over 600,000 patients worldwide annually, with the incidence rate increasing over the past decade. Metastatic urothelial carcinoma (mUC) has a poor prognosis, with the 5-year survival rate estimated to be as low as 10-15%.Nectin-4 is highly expressed in mUC. It is a clinically validated target for mUC with enfortumab vendotin (EV) and pembrolizumab combination as the newly established SOC for first-line metastatic and locally advanced UC. TROP2 is also highly expressed in UC, and sacituzumab govetecan (SG) has shown therapeutic activity in later-line mUC. Nectin-4xTROP2 bsADC aims to target these two clinically validated targets in mUC to further improve efficacy and reduce toxicity.
Method: Fully human antibodies against Nectin-4 and TROP2 were generated with Biocytogen's RenLite ® transgenic mice. We selected the arms of the bispecific antibody based on their internalization activities in constructing and evaluating the bispecific antibody in a 1+1 format. The bispecific antibody was conjugated to both vcMMAE at DAR of 4 and Biocytogen's proprietary linker-payload BLD1102 at DAR of 4, respectively. BLD1102 is composed of a novel TOP1 inhibitor payload and a highly hydrophilic and enzyme-cleavable linker. The resulting ADCs were tested in CDX and PDX tumor models in mice, along with relevant benchmark ADCs for anti-tumor activity.
Results: We selected the arms based on their internalization activities, with the nectin-4 arm and the TROP2 arm showing enhanced internalization capability in the format of 1+1 bispecific antibody vs the respective monovalent parental arms, suggesting cooperative interactions of the two arms. Consistent with this in vitro observation, the vcMMAE conjugated bispecific ADC (bsADC) exhibited markedly increased anti-tumor activity compared with the monovalent parental ADCs in mouse CDX/PDX models. BCG039, the BLD1102-conjugated bsADC, also demonstrated tumor growth inhibition superior to benchmark anti-nectin-4 and certain benchmark anti-TROP2 ADCs. The bispecific antibody has excellent developability and is now in CMC development.
Conclusion: BCG039, a bsADC targeting Nectin-4 and TROP2, showed superior anti-tumor efficacy in mice compared to single-targeting parental ADCs and relevant benchmark ADCs. The cooperative interaction of the two arms may also help reduce the toxicity observed with single-targeting ADCs against these targets in mUC.
利益披露 Disclosure
F. An, None..
L. Yang, None..
C. Shang, None..
J. Han, None..
Y. Yang, None..
F. An, None.