Development of broadly neutralizing antibodies against Omicron variants from existing neutralizing antibodies in clinical trials.

BACKGROUND: The introduction of new SARS-CoV-2 Omicron strains has made it extremely difficult to create broadly neutralizing antibodies (nAbs) with assured therapeutic potential. Currently approved neutralizing antibodies have displayed substantially decreased or abolished efficacy against emerging Omicron variants including XBB and BQ.1 Due to the potential of reinfection from new emerging VOCs, this emphasizes the urgent need for developing widely active mAbs that offer preventive and therapeutic advantages to high-risk patients. Here, we aimed to investigate the feasibility of redirecting existing mAbs which are in late-stage development in clinical trials against new variants of SARS-CoV-2. METHODS: In vitro affinity maturation libraries against BA.2 RBD were constructed based on neutralizing antibodies P5-22 and P14-44 developed by Innovent Biologics as components of IBI314 (ClinicalTrials.gov Identifier: NCT05162365). Yeast surface display and flow cytometry sorting were utilized to screen antibodies with improved affinity. The selected antibodies were characterized by binding kinetics analysis. Their neutralization potency against SARS-CoV-2 variants was evaluated by pseudovirus neutralization assay and focus reduction neutralization test. Bispecific antibodies were designed in different formats using affinitymatured Fabs. The prophylactic and therapeutic efficacy of antibodies were examined in hACE2 transgenic mice infected with BA.2.3. RESULTS: By in vitro affinity maturation of two nAb P5-22 and P14-44, we obtained antibodies broadly neutralizing pre-Omicron strains and BA.1/BA.2 variants. A bispecific 2 + 2 antibody showed further neutralization potency against BA.4/BA.5 even XBB and BQ1.1. These bispecific antibodies showed potent therapeutic and prophylactic potency in authentic Omicron virus challenge in mouse models in vivo. CONCLUSIONS: Together, our approach revealed the possibility of engineering of existing antibodies to broad-spectrum mAbs as potential therapeutic or prophylactic agents for COVID-19.