SA55 for COVID-19

SARS-CoV-2 monoclonal antibodies remain the only option for the prevention or treatment of COVID-19 for those with immunodeficiencies or drug interactions with antiviral agents. Here, we assess the neutralizing activity of the authorized antibody pemivibart and the candidate antibody SA55 against major historical and currently dominant viral variants, including the JN.1 subvariants KP.3.1.1 and XEC. Our findings show that SA55 demonstrates broad neutralizing potency while pemivibart exhibits reduced neutralizing activity against currently dominant variants. Then we employ replication-competent vesicular stomatitis virus with the JN.1 spike (rVSVΔG-JN.1) to select escape variants of SA55. Following this, we conduct a systematic comparison of escape profiles for these two antibodies, revealing that SA55 is remarkably resilient to escape mutations under antibody selection, which is consistent with our SPR data indicating that SA55 possesses a substantially stronger binding affinity. Moreover, an immunobridging analysis suggests that SA55 may have superior clinical efficacy to pemivibart in preventing SARS-CoV-2 infection under the current variant landscape. Together, this work highlights the promise of SA55 as a potential therapeutic option in the prevention and treatment of COVID-19, especially in immunocompromised populations.

Pemivibart is a monoclonal antibody therapy currently under Emergency Use Authorization for the for the pre-exposure prophylaxis of coronavirus disease 2019 (COVID-19) in adults and adolescents over 12 years of age with certain immunocompromised conditions. As a part of the overall monitoring strategy for the activity of pemivibart, the antibody is regularly evaluated against emerging variants of SARS-CoV-2 using pseudovirus neutralization assays. Recent clinical data from Invivyd demonstrates that the PhenoSense pseudovirus assays carried out at Monogram Biosciences have been a reliable and consistent predictor of continued pemivibart clinical activity against SARS-COV-2 variants that have predominated across the timespan that includes the CANOPY clinical trial and the post-EUA authorization period. Additionally, new potential antibodies based upon the structural framework of pemivibart are continuously under evaluation. Fifteen of these yeast-produced pemivibart-like antibodies were tested for neutralization activity against recent variants KP.3 and KP.3.1.1. Like pemivibart, all 15 maintained activity against KP.3.1.1, with the change in IC50 averaging 2.51-fold +/- 0.7 compared to KP.3. Four pemivibart-like antibodies were also tested against the XEC variant, with the change in IC50 averaging 3.01-fold compared to KP.3. These data suggest continued activity for pemivibart and pemivibart-like antibodies against KP.3.1.1 and XEC, recent variants containing N-terminal domain modifications.

Background: First-generation anti-SARS-CoV-2 monoclonal antibodies (mAbs) used for prophylaxis or therapeutic purposes in immunocompromised patients have been withdrawn because of the emergence of resistant Omicron variants. In 2024, 2 novel mAbs, VYD222/Pemivibart and AZD3152/Sipavibart, were approved by health authorities, but their activity against contemporary JN.1 sublineages is poorly characterized. Methods: We isolated authentic JN.1.1, KP.1.1, LB.1, and KP.3.3 viruses and evaluated their sensitivity to neutralization by these mAbs in 2 target cell lines. Results: Compared to ancestral strains, VYD222/Pemivibart remained moderately active against JN.1 subvariants, with a strong increase of 50% Inhibitory Concentration (IC50), reaching up to 3 to 15 µg/mL for KP.3.3. AZD3152/Sipavibart neutralized JN.1.1 but lost antiviral efficacy against KP.1.1, LB.1, and KP.3.3. Conclusions: Our results highlight the need for a close clinical monitoring of VYD222/Pemivibart and raise concerns about the clinical efficacy of AZD3152/Sipavibart.