Sotrovimab, a monoclonal antibody derived from S-309, targets a conserved epitope in the SARS-CoV-2 Spike protein. It was initially effective against various SARS-CoV-2 variants, including Alpha, Epsilon, Gamma, and Zeta, and showed high efficacy in clinical trials for outpatient treatment of mild to moderate COVID-19. However, its effectiveness declined against later variants, particularly BA.2.86*, due to mutations such as K356T, which prevent binding to the Spike protein. Sotrovimab was deauthorized by the FDA in 2022 due to reduced efficacy against BA.2, but continued use was advocated by some authorities despite its limited effectiveness against newer variants. Real-world data suggest that sotrovimab can reduce hospitalization and mortality in high-risk patients, but its use is now limited due to the emergence of resistant variants. Sotrovimab's resistance to viral evolution highlights the need for developing more resilient monoclonal antibodies and combination therapies to combat emerging variants. Despite its initial success, sotrovimab's eventual ineffectiveness underscores the challenges in maintaining therapeutic efficacy against rapidly evolving viruses. The study emphasizes the importance of designing therapies that minimize resistance and the need for ongoing research into more effective treatments.Sotrovimab, a monoclonal antibody derived from S-309, targets a conserved epitope in the SARS-CoV-2 Spike protein. It was initially effective against various SARS-CoV-2 variants, including Alpha, Epsilon, Gamma, and Zeta, and showed high efficacy in clinical trials for outpatient treatment of mild to moderate COVID-19. However, its effectiveness declined against later variants, particularly BA.2.86*, due to mutations such as K356T, which prevent binding to the Spike protein. Sotrovimab was deauthorized by the FDA in 2022 due to reduced efficacy against BA.2, but continued use was advocated by some authorities despite its limited effectiveness against newer variants. Real-world data suggest that sotrovimab can reduce hospitalization and mortality in high-risk patients, but its use is now limited due to the emergence of resistant variants. Sotrovimab's resistance to viral evolution highlights the need for developing more resilient monoclonal antibodies and combination therapies to combat emerging variants. Despite its initial success, sotrovimab's eventual ineffectiveness underscores the challenges in maintaining therapeutic efficacy against rapidly evolving viruses. The study emphasizes the importance of designing therapies that minimize resistance and the need for ongoing research into more effective treatments.