Phd Student The University of Hong Kong, China (People's Republic)
Abstract: The efficacy of VIR-7831, a class 3 anti-SARS-CoV-2 monoclonal antibody (mAb), was verified in multiple clinical trials; yet cell line-based neutralization assays underestimated its potency, leading to the erroneous withdrawal from clinical use. Thus, there is an unmet demand for a biologically relevant neutralization assay to provide a correlate of in vivo protection. We sought to develop organoid-based neutralization assays to measure the potency of mAbs against coronaviruses, based on the high biological relevance of nasal organoids and the robust organoid culture system. Due to the biologically relevant low ACE2 expression, nasal organoid-based neutralization assays adequately recapitulated the real-world effectiveness of VIR-7831. Most class 3 SARS-CoV-2 mAbs, especially those not blocking RBD-ACE2 binding, exhibited a higher potency in the organoids than in the cell lines. Moreover, due to the high TMPRSS2 expression in nasal organoids, reminiscent of native human respiratory epithelial cells, organoid-based neutralization assays reproduced the in vivo protection of S2 mAbs, which was not manifested in cell lines. Collectively, the robust organoid culture system and biologically relevant expression profile of ACE2 and TMPRSS2 grant nasal organoids to present a unique and optimal correlate of in vivo protection of neutralizing mAbs. The organoid-based neutralization assays, superior to the conventional cell-line-based neutralization assays, can recapitulate and predict the real-world efficacy of mAbs.
