Abstract LB031: SHR-A1811, a novel anti-HER2 ADC with superior bystander effect, optimal DAR and favorable safety profiles

Abstract

Abstract Current clinical HER2-targeting ADCs, especially T-DXd, have shown strong efficacy in HER2-expressing/mutant cancers, however, with adverse events such as hematologic toxicities and interstitial lung disease (ILD)/pneumonitis. Here we presented a potential best-in-class HER2-directed ADC, SHR-A1811, which was composed of trastuzumab, a stable and cleavable linker, and a novel topoisomerase I inhibitor payload (SHR9265). SHR9265 was a delicately selected exatecan derivative with a better liposolubility and cellular permeability: SHR9265 had a higher AlogP value than SHR7971, synthesized using published DXd structure (3.67 vs. 2.72). Consistently, SHR9265 showed ~5 times higher membrane permeability (PAMPA model) at pH5 and pH7.4. Cell killing activity of SHR9265 was ~3 times more potent than SHR7971. SHR-A1811 had a drug-to-antibody ratio (DAR) of 5.7, and showed HER2-dependent growth inhibition against various breast cancer and gastric cancer cell lines. In the bystander killing system, SHR-A1811 was able to kill both SK-BR-3 (HER2+) and MDA-MB-468 (HER2-) cells when co-cultured, with the IC50 on MDA-MB-468 of 0.28 nM. The in vitro efficacy of SHR-A1811 was comparable with anti-Her2-SHR9265 (DAR 7.5) and ADC1 (synthesized using T-DXd structure), and stronger than anti-Her2-SHR9265 (DAR 3.5). In SK-BR-3 (HER2 high), JIMT-1 (HER2 moderate) and capan-1 (HER2 low) xenograft models, SHR-A1811 treatment resulted in a dramatic and sustained inhibition of tumor growth. A significantly stronger antitumor activity was observed for SHR-A1811 than ADC1 under the same dosages. Moreover, SHR-A1811 showed good stability and improved safety profiles, presumably due to the proper steric hindrance which was purposely designed on the payload (SHR9265). Less than 2% of payload release was observed in human plasma after a 21-day incubation. The HNSTD of SHR-A1811 in cynomolgus monkeys was 40mpk with thymus as the main target organ. No death and lung lesions were observed at dose levels up to 70mpk for 42 days, while ADC1 led to one male cynomolgus monkey death on day 10 at 70mpk with multiple lung damages. These findings were consistent with safety profiles observed in a multi-center, dose-escalation phase I clinical trial (NCT0444620). Patients with different solid tumor types received initial intravenous doses of SHR-A1811 from 1 to 8.0 mg/kg. Only trace amount of free toxin was detected. The Cmax of payload was 3.85 ng/ml at 8mg/kg of SHR-A1811. The incidence of G2 ILD was < 2.5% and the treatment discontinuation rate was 5.1% across doses. In summary, with a highly permeable payload, optimized DAR, great potency and better clinical safety profiles, SHR-A1811 has demonstrated the best-in-class potential. Currently SHR-A1811 has entered phase II and phase III clinical studies for breast cancer, gastric cancer, colorectal cancer, and NSCLC (NCT05424835, NCT05482568, NCT04818333, NCT05349409). Citation Format: Ting Zhang, Lingfeng You, Jianyan Xu, Junzhao Yin, Bolei Qu, Yuchang Mao, Beibei Fu, Dan Cao, Linda Zhao, Jun Feng, Min Hu, Feng He. SHR-A1811, a novel anti-HER2 ADC with superior bystander effect, optimal DAR and favorable safety profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB031.