Organoid-based evaluation of SA55 and Pemivibart against evolving SARS-CoV-2 variants.

Pemivibart, a class 1/4 monoclonal antibody (mAb), is currently the only FDA-authorized SARS-CoV-2 mAb under an Emergency Use Authorization (EUA) in clinical use. The emergence of subvariants, including KP.3.1.1 and XFG, raises concerns about antibody efficacy. SA55, a fully human class 1/4 mAb, is currently under clinical trial, including a nasal spray formulation. Using the well-validated organoid-based neutralization assays, we compared the potency and breadth of Pemivibart and SA55. Our results demonstrated a significant decrease in Pemivibart's activity against KP.3.1.1 and XFG, with an approximately 80-fold increase in IC50 relative to the ancestral strain. Given KP.3.1.1's strong reliance on the TMPRSS2 pathway for cell entry, we further demonstrated that combinational treatment with Pemivibart and the broad-spectrum S2 antibody results in potent neutralization. Notably, SA55 maintained potent neutralization (IC50 ≤ 40 ng/mL) across all tested variants. Topical administration, which models nasal spray, dramatically suppressed viral replication of BA.5.2 and XFG in organoid models. Our findings evidence the high potency of SA55, supporting its potential for clinical application against emerging SARS-CoV-2 variants.