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

Abstract 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.