Current Status and Perspectives of Therapeutic Antibodies Targeting the Spike Protein S2 Subunit against SARS-CoV-2

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has devastated public health and the global economy. New variants are continually emerging because of amino acid mutations within the SARS-CoV-2 spike protein. Existing neutralizing antibodies (nAbs) that target the receptor-binding domain (RBD) within the spike protein have been shown to have reduced neutralizing activity against these variants. In particular, the recently expanding omicron subvariants BQ 1.1 and XBB are resistant to nAbs approved for emergency use by the United States Food and Drug Administration. Therefore, it is essential to develop broad nAbs to combat emerging variants. In contrast to the massive accumulation of mutations within the RBD, the S2 subunit remains highly conserved among variants. Therefore, nAbs targeting the S2 region may provide effective cross-protection against novel SARS-CoV-2 variants. Here, we provide a detailed summary of nAbs targeting the S2 subunit: the fusion peptide, stem helix, and heptad repeats 1 and 2. In addition, we provide prospects to solve problems such as the weak neutralizing potency of nAbs targeting the S2 subunit.