Publication date: Jul 23, 2025

Introduction SARS-CoV-2 virus inflicts a major ongoing medical toll via acute infection with substantial morbid and mortal outcomes, as well as post-acute sequelae. Multiple SARS-CoV-2 RBD-directed mAbs, which emulate native human immunobiology following infection, have been developed, authorized, and demonstrated substantial efficacy for treatment of COVID-19. However, rapid virus evolution challenges traditional development pathways, as non-susceptible variants can emerge faster than development and regulatory review can be completed. Fortunately, mAb antiviral activity across viral variants can be measured via clinical serum virus neutralizing antibody titers that correlate to demonstrated clinical outcomes from historical mAbs and serve as surrogate biomarkers for efficacy. This analytic immunobridging approach is useful for rapid assessment of novel mAb efficacy, especially for mAbs engineered from a clinically established molecular ancestor. Immunobridging is commonly used in vaccine development and supported the Emergency Use Authorization (EUA) of pemivibart, a mAb targeted to the spike protein of SARS-CoV-2 for prevention of COVID-19 in immunocompromised patients. We therefore applied a similar framework to evaluate pemivibart for the treatment of acute COVID-19, aiming to address the urgent unmet needs of immunocompromised patients who remain vulnerable despite vaccination and antiviral therapies, but failed to secure FDA authorization. Methods Three complementary methods were used to evaluate immunobridging of pemivibart against 4 dominant variants (JN.1, KP.3.1.1, XEC, and LP.8.1) for the treatment of COVID-19: 1) strict immunobridging of neutralizing antibody titers of pemivibart to its parent molecule adintrevimab, 2) benchmarking comparison of neutralizing antibody titers of pemivibart to other historical mAbs with prior demonstrated efficacy in the treatment of COVID-19, and 3) dose-response analysis of pemivibart to comparator mAbs based on a published meta-analysis. Results Pemivibart demonstrated strict immunobridging to adintrevimab from 4 to >14 days, depending on variant analyzed. Neutralizing titers of pemivibart across variants were 4-12 fold higher than titers demonstrated for sotrovimab and less than titers for other historical IV-administered mAbs throughout a 14-day analysis period. The dose-response analysis predicted pemivibart to have equivalent efficacy to all other comparator mAbs. Conclusion Following a similar approach to prevention, immunobridging was demonstrated for pemivibart for the treatment of COVID-19 using multiple complementary methods and suggesting substantial antiviral activity that would accelerate and amplify the native human antibody response. This development methodology, which draws on quantitative virology, biological mechanism, and the U.S. regulatory response to our initial approach provides a road map for accelerating novel COVID-19 treatment options in the face of a changing variant landscape.

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