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The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) heavily burdens human health. Multiple neutralizing antibodies (nAbs) have been issued for emergency use or tested for treating infected patients in the clinic. However, SARS-CoV-2 variants of concern (VOC) carrying mutations reduce the effectiveness of nAbs by preventing neutralization. Uncoding the mutation profile and immune evasion mechanism of SARS-CoV-2 can improve the outcome of Ab-mediated therapies. In this review, we first outline the development status of anti-SARS-CoV-2 Ab drugs and provide an overview of SARS-CoV-2 variants and their prevalence. We next focus on the failure causes of anti-SARS-CoV-2 Ab drugs and rethink the design strategy for developing new Ab drugs against COVID-19. This review provides updated information for the development of therapeutic Ab drugs against SARS-CoV-2 variants.