Journal Article

SHR-A1811, a novel anti-HER2 antibody–drug conjugate with optimal drug-to-antibody ratio, efficient tumor killing potency, and favorable safety profiles

Wen, Weiyun, Xu, Zhibin, Sun, Xing, Zhang, Ting, Mao, Yuchang, Sun, Jiakang, He, Feng, Feng, Jun, Yin, Junzhao, Xu, Jianyan, Hu, Min, Fu, Beibei, Tu, Shiwei, Gao, Yun, Xue, Zhendong, Cao, Dan, You, Lingfeng, Zheng, Hanwen, Qu, Bolei

2025

Overview

HER2-targeting antibody–drug conjugates (ADCs), especially trastuzumab deruxtecan (T-DXd), have revolutionized the treatment landscape of HER2-expressing or mutant cancers. However, undesired adverse events are still inevitable and it is necessary to discover a HER2-directed ADC with better safety profiles. SHR-A1811 is composed of trastuzumab, a cleavable linker and a novel topoisomerase I inhibitor, SHR169265. The results indicated that SHR169265 shows better permeability, strong cytotoxicity and faster systemic clearance than DXd analog (SHR197971). The drug-to-antibody ratio (DAR) of SHR-A1811 was optimized as 6 via balancing efficacy and toxicity. SHR-A1811 showed HER2-dependent growth inhibition against various cell lines and desirable bystander killing capability. SHR-A1811 led to tumor growth inhibition or even regression in a dose-dependent manner, at least comparable as HRA18-C015 (a synthesized T-DXd) and anti-HER2-SHR169265 (DAR 8) in multiple mouse xenograft models with a range of HER2 expression levels. SHR-A1811 exhibited a good pharmacokinetics profile, outstanding stability in plasma across different species and a favorable preclinical safety profile. The highest non-severely toxic dose (HNSTD) in cynomolgus monkeys was 40 mg/kg with thymus as the main target organ. The above results suggested that SHR-A1811 is a potential best-in-class anti-HER2 ADC with a highly permeable payload, optimized DAR, great potency and better safety profiles. Currently SHR-A1811 has entered phase II and phase III clinical studies for breast cancer, gastric cancer, colorectal cancer, and NSCLC.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Animal models / Animals / Antibodies / Antibodies, Monoclonal, Humanized - pharmacology / Antibody-drug conjugates / Biology and Life Sciences / Biopharmaceutics / Breast cancer / Camptothecin - analogs & derivatives / Camptothecin - pharmacology / Carbon dioxide / Care and treatment / Cell Line, Tumor / Colorectal cancer / Colorectal carcinoma / Conjugates / Cytotoxicity / Diagnosis / DNA topoisomerase / Dosage and administration / Drug dosages / ErbB-2 protein / Female / Gastric cancer / Health aspects / Humans / Humidity / Immunoconjugates - adverse effects / Immunoconjugates - chemistry / Immunoconjugates - pharmacokinetics / Immunoconjugates - pharmacology / Laboratory animals / Lung diseases / Medicine and Health Sciences / Mice / Mice, Inbred BALB C / Mice, Nude / Peptides / Permeability / Pharmacokinetics / Rats / Receptor, ErbB-2 - antagonists & inhibitors / Receptor, ErbB-2 - immunology / Receptor, ErbB-2 - metabolism / Safety / Toxicity / Trastuzumab / Trastuzumab - chemistry / Trastuzumab - pharmacokinetics / Trastuzumab - pharmacology / Tumors / Xenograft Model Antitumor Assays / Xenotransplantation