Engineered Dual‐Function Antibody‐Like Proteins to Combat SARS‐CoV‐2‐Induced Immune Dysregulation and Inflammation

Complement dysregulation and immune hyperactivation are pivotal factors contributing to the mortality associated with SARS-CoV-2 infection. Engineered Antibody-like proteins (ALPs) targeting the SARS-CoV-2 spike protein are engineered to address immune dysregulation in COVID-19. In this study, Lectifitin-36 and Lectifitin-41, two such ALPs, are developed using cDNA display technology. These ALPs demonstrate strong binding affinity for the spike protein and effectively inhibit its interaction with ACE2 and several C-type lectins, including MBL, DC-SIGN, and L-SIGN. Both in vitro and in vivo analyses reveal that Lectifitin-36 and Lectifitin-41 suppress complement activation via the lectin pathway, reduce neutrophil extracellular trap (NET) formation, and attenuate hyper-inflammatory responses. In mouse models, Lectifitin-36 and Lectifitin-41 significantly mitigate inflammation, NETosis, and lung tissue damage induced by the spike protein. These results suggest that these ALPs hold promise as therapeutic candidates for alleviating SARS-CoV-2-induced immune dysfunction, with the potential to reduce severe COVID-19 outcomes and long-term sequelae. This study underscores the therapeutic potential of targeting spike protein-mediated immune modulation as an innovative approach to combat COVID-19.