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The recurrent emerging of novel viral variants of concern (VOCs) with evasion of preexisting antibody immunity upholds severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case numbers and maintains a persistent demand for updated therapies. We selected the patient-derived antibody CV38-142 based on its potency and breadth against the VOCs Alpha, Beta, Gamma, and Delta for preclinical development into a therapeutic. CV38-142 showed in vivo efficacy in a Syrian hamster VOC infection model after post-exposure and therapeutic application and revealed a favorable safety profile in a human protein library screen and tissue cross-reactivity study. Although CV38-142 targets the same viral surface as sotrovimab, which maintains activity against Omicron, CV38-142 did not neutralize the Omicron lineages BA.1 and BA.2. These results highlight the contingencies of developing antibody therapeutics in the context of antigenic drift and reinforce the need to develop broadly neutralizing variant-proof antibodies against SARS-CoV-2., Competing Interests: The German Center for Neurodegenerative Diseases (DZNE) and Charité-Universitätsmedizin Berlin have filed a patent application (application number: PCT/EP2021/064,352) on antibodies for the treatment of SARS-CoV-2 infection on which J.K., S.M.R., H.-C.K., E.S.-S., L.E.S., V.M.C., and H.P. are named as inventors. V.M.C. is named together with Euroimmun GmbH on a patent application filed recently regarding the diagnostic of SARS-CoV-2 by antibody testing. S.E., V.N., M.M., S.K., S.H., P.H., and U.J. are employees of Miltenyi Biotec B.V. & Co. KG., (© 2023 The Author(s).)