Optimization of mRNA-based antibody expression targeting SFTSV Gn

다국어 초록 (Multilingual Abstract)

Severe fever with thrombocytopenia syndrome (SFTS) a tick‑borne infectious disease. It was first reported in China in 2009 and is caused by the severe fever with thrombocytopenia syndrome virus (SFTSV). It is characterized by high fever, thrombocytopenia, and leukopenia, and is frequently associated with a high mortality rate. Currently, no vaccines or specific antiviral treatments have been approved. In response to this unmet medical need, considerable efforts have been devoted to developing antibody-based therapeutics and vaccines against SFTSV. Neutralizing antibodies isolated from patients have been shown to recognize the viral Gn glycoprotein and effectively inhibit SFTSV infection. Recent studies have also demonstrated that mRNA-based delivery of antibodies can confer protective efficacy in vivo. Motivated by the concept that the antibody structure may substantially influence expression efficiency, neutralization potency, and pharmacokinetics, we aimed to identify the most effective structures for SFTSV-neutralizing antibodies. In this study, we compared mRNA-LNPs encoding monoclonal antibodies targeting the Gn glycoprotein of SFTSV in three structures: (1) two separate mRNAs for the heavy and light chains (H/L), (2) a single-chain that links the heavy and light chains via a flexible peptide (H+L), and (3) an scFv fused to an Fc domain (scFv). These structures were evaluated for in vitro expression and neutralization. The H+L structure showed superior neutralizing activity. In IFNAR knockout mice challenged with SFTSV, this construct significantly improved survival. Collectively, these findings indicate that modulation of the antibody structural format encoded within the mRNA sequence can enhance antibody expression levels, antigen-binding capacity, and neutralizing activity. These results demonstrate the therapeutic potential of mRNA-based monoclonal antibodies and highlight the impact of antibody structures on the efficacy of mRNA-based therapeutics.

목차 (Table of Contents)

• Ⅰ. Abstract 1
• Ⅱ. Introduction 3
• Ⅲ. Materials and Methods 23
• Ⅳ. Results 36
• Ⅴ. Discussion 52
• Ⅵ. Reference 59
• Ⅶ. 국문 논문제출서 73
• Ⅷ. 국문 인준서 74
• Ⅸ. 국문 초록 75