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. 2025 Jun 26;20(6):e0326691.
doi: 10.1371/journal.pone.0326691. eCollection 2025.

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

Ting Zhang  1 , Jianyan Xu  1 , Junzhao Yin  1 , Yun Gao  1 , Hanwen Zheng  1 , Beibei Fu  1 , Jiakang Sun  1 , Zhibin Xu  1 , Shiwei Tu  1 , Yuchang Mao  1 , Weiyun Wen  1 , Bolei Qu  1 , Lingfeng You  1 , Zhendong Xue  1 , Xing Sun  2 , Dan Cao  1 , Jun Feng  1 , Min Hu  1 , Feng He  1
Affiliations

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

Ting Zhang et al. PLoS One. .

Abstract

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.

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Conflict of interest statement

This study was funded by Shanghai Hengrui Pharmaceutical Co., Ltd., a leading company in China focuses on new drug development for multiple diseases to address unmet medical needs. SHR-A1811 is developed by Shanghai Hengrui and multiple phase II and III clinical trials are being conducted. The result of a global phase I trial has been published in Journal of Clinical Oncology. The authors, Ting Zhang, Jianyan Xu, Junzhao Yin, Yun Gao, Hanwen Zheng, Beibei Fu, Jiakang Sun, Zhibin Xu, Shiwei Tu, Yuchang Mao, Weiyun Wen, Bolei Qu, Lingfeng You, Zhendong Xue, Dan Cao, Jun Feng, Min Hu, and Feng He are paid employees of Shanghai Hengrui Pharmaceutical Co., Ltd. Please note this does not alter our adherence to PLOS ONE policies on sharing data and materials, and the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Figures

Fig 1
Fig 1. Structure and bystander killing effect of anti-HER2-SHR169265 ADCs.
(A) Structure illustration of SHR-A1811. SHR-A1811 is composed of trastuzumab, a stable and cleavable linker, and a topoisomerase I inhibitor payload SHR169265, with DAR at 6. (B) Bystander killing effect of anti-HER2-SHR169265 ADCs. SK-BR-3 (HER2-positive) and MDA-MB-468 (HER2-negative) cells were co-cultured and treated. For comparison, MDA-MB-468 cells were cultured alone and treated in the same way. Cell numbers of SK-BR-3 and MDA-MB-468 cells after treatment with 10 nM of ADCs for 5 days were analyzed. (C) The inhibitory effect of ADCs on MDA-MB-468 in the co-culture system for bystander killing. Cells were treated with various doses of ADCs for 3 days. Data represented three independent experiments. *P < 0.05 versus HRA18-C015.
Fig 2
Fig 2. Antitumor effect of anti-HER2-SHR169265 ADCs.
(A) HER2 IHC staining on NCI-N87, JIMT-1 and Capan-1 xenografted tumors. (B) Comparison of antitumor effect of anti-HER2-SHR169265 ADCs with different DAR values in JIMT-1 xenograft model. (C-E) Antitumor effect of SHR-A1811 in NCI-N87 (C), JIMT-1 (D) and Capan-1 (E) xenograft models. All of the tumor-bearing mice were intraperitoneally administered with ADCs single dose except JIMT-1 xenograft model in panel D, with every week administration for two weeks. Arrows indicate days of administration. The mean tumor volume and SEM (n = 6-8) were represented on the graph, and TGI% calculated for each treatment group. *P < 0.05, **P < 0.01, ***P < 0.001 versus vehicle. (F) The concentration of SHR169265 and SHR167971 in NCI-N87 tumors after single dose of SHAR-A1811 and HRA18-C015. (G) PK/PD relationship of SHR-A1811 in NCI-N87 model. The tumoral SHR169265 concentration and cleaved PARP level were measured at 8, 24, 72 and 168 hours after single dose of ADC. Data shown as means from two tumor samples.
Fig 3
Fig 3. Pharmacokinetics and plasma stability of SHR-A1811.
(A) Pharmacokinetics of SHR-A1811 in rats. SHR-A1811 were intravenously administered at the dose of 3 mg/kg. Concentrations of SHR-A1811 and total antibody were measured. (B) In vitro stability of SHR-A1811 in plasma of different species. SHR-A1811 was incubated in mouse, rat, monkey, and human plasma at 37°C for up to 21 days. The concentrations of released payload were detected, and release rates (%) was calculated.
Fig 4
Fig 4. Toxicokinetics of SHR-A1811 in cynomolgus monkeys.
SHR-A1811 was intravenously administered at the dose of 40 mg/kg every 3 weeks for 5 doses (n = 10). SHR-A1811, total antibody and payload concentrations were measured after the first and fourth doses. Data shown as means from ten samples.
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