PO.CL05.03 · 临床研究

用于实体瘤靶向治疗的差异化EGFR/PDL1双特异性ADC的工程化设计与临床前开发

Engineering and preclinical development of a differentiated EGFR/PDL1 bispecific ADC for the targeted therapy of solid tumors

编号 3807 展板 22 时间 4/20 02:00–05:00 区域 Section 43 主讲 Liang Tian, PhD

分会场 Combination Immunotherapies

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作者与单位 Authors & Affiliations

Liang Zhu, Chen Chuan, Mei Tian, Dandan Liu, Jiyuan Tian, Lisha Dong, Yongxin Shang, Rongmei Yan, Kezhen Ye, Liang Tian, Jian Peng, Zhenping Zhu

Earendil Labs, Wilmington, DE

摘要 Abstract

中文摘要

EGFR和PDL1均为多种恶性肿瘤公认的治疗靶点。然而，它们的治疗疗效仍然有限，因为许多患者要么原发难治，要么在治疗过程中产生耐药。EGFR和PDL1在多种肿瘤中常共表达，它们在促进肿瘤进展和免疫逃逸中发挥关键作用。值得注意的是，PDL1的表达受EGFR信号调控，且已有报道EGFR与PDL1信号之间存在显著的串扰。在本研究中，我们开发了一种同时靶向EGFR和PDL1的双特异性抗体（bsAb）。该bsAb对PDL1+/EGFR+癌细胞表现出增强的结合亲合力，具有更高的内化效率，以及更强效的EGFR导向的PD1/PDL1相互作用阻断。通过与多种细胞毒性载荷偶联，生成了若干bsAb ADC。体外数据表明，先导bsADC诱导了强效的抗肿瘤活性和强烈的旁观者杀伤活性。重要的是，在PDL1+人抗原呈递细胞上未观察到免疫毒性。体内疗效研究表明，与MRG003类似物（一种抗EGFR ADC）和处于临床阶段的PDL1V类似物（一种抗PDL1 ADC）相比，先导bsADC在多个CDX模型中取得了更优的抗肿瘤活性。

查看英文原文 English abstract

Both EGFR and PDL1 are well-established therapeutic targets for a broad range of malignancies. Nevertheless, their therapeutic efficacy remain limited, as many patients are either refractory to or develop resistance during the course of treatment. EGFR and PDL1 are frequently co-expressed in multiple tumors, where they play key roles in promoting tumor progression and immune evasion. Notably, PDL1 expression is modulated by EGFR signaling, and the significant crosstalk between EGFR and PDL1 signaling has been reported. In this study, we developed a bispecific antibody (bsAb) targeting both EGFR and PDL1. The bsAb demonstrated enhanced binding avidity towards PDL1+/EGFR+ cancer cells, with higher efficiency of internalization, and more potent EGFR‑directed blockade of PD1/PDL1 interaction. Several bsAb ADCs were generated by conjugating with various cytotoxic payloads. In vitro data demonstrated that the lead bsADC induced potent antitumor activity and strong bystander killing activity. Importantly, no Immunotoxicity was observed on PDL1+ human antigen‑presenting cells. In vivo efficacy studies demonstrated that the lead bsADC achieved superior antitumor activity compared with MRG003 analog (an anti-EGFR ADC) and the clinical-stage PDL1V analog (an anti-PDL1 ADC) in multiple CDX models.

利益披露 Disclosure

L. Zhu, None.. C. Chuan, None.. M. Tian, None.. D. Liu, None.. J. Tian, None.. L. Dong, None.. Y. Shang, None.. R. Yan, None.. K. Ye, None.. L. Tian, None.. J. Peng, None.. Z. Zhu, None.

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