Raffaele Colombo, Director of Medicinal Chemistry at Zymeworks, shared on X:
“Adding some more color. For a DAR4 ADC with moderate stability, comparison of total antibody (TAb, green) and ADC PK (black) highlights deconjugation. SHR-A2102 illustrates this well! Green and black lines diverge.
Original data from the paper: PK replotted for 6 and 8 mg/kg.
Pointing out a common mistake in assessing ADC stability from this recente SHR-A2102 paper. SHR-A2102 utilized an MC-GGFG linker, which is not fully stable. Free payload concentration is NOT a right assessment of ADC stability!”
Title: Re-evaluating antibody-drug conjugate linker stability: assessment, interpretation, and clinical translation
Authors: R. Colombo, S.D. Seredick , S.D. Barnscher, J.R. Rich.
Read the full article.
“Phase 1 of SHR-A2102 in patients (N=395) advanced solid tumours published on The Lancet Oncology Including NSCLC, HR+/HER2- BC, TNBC, ESCC, HNSCC Tox typical of a TOP1i ADC Interesting discussion about biomarkers (359 patients included in the analysis)!
But don’t use this method for DAR8 ADCs with moderate stability! The reason is simple: difference between TAb and ADC PK reflects only DAR0 species. DAR8 ADCs generate DAR2-3 species, but not necessarily DAR0.
Always better to use TAb vs. AcDrug!”
Title: SHR-A2102, a nectin-4 directed antibody-drug conjugate, in patients with pretreated advanced solid tumours: a multicentre, single-arm, phase 1 trial
Authors: Runbo Zhong, Huangming Hong, Min Yan, Qiming Wang, Yan Zhang, Qiongyu Lan, Yongzhong Luo, Ling Zhang, Haipeng Xu, Sanxing Guo, Wei Guom, Jie Ma, Longzhen Zhang, Lin Wu, Zhigang Liu, Wei He, Yubei Sun, Kai Chen, Jiangqiong Huang, Guang Han, Weiqi Nian, Ming Zhang, Shengxiang Ren, Rong Qiao, Xiang Li, Meijing Yu, Jin Hu, Yanhua Huang, Li Song, Wei Shi, Hua Zhong.
Read the full article.
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