This study pioneers the in vivo validation of synthetic DNA-encoded monoclonal antibody (DMAb) technology in humans, demonstrating its long-term stable expression, broad neutralizing activity, and favorable tolerability, offering novel insights for future antibody therapies.
Literature Overview
The article titled "Safety and pharmacokinetics of SARS-CoV-2 DNA-encoded monoclonal antibodies in healthy adults: a phase 1 trial" published in Nature Medicine reviews and summarizes the safety, tolerability, and pharmacokinetics of synthetic DNA-encoded monoclonal antibodies (DMAbs) in healthy adults. Two DMAbs (AZD5396 and AZD8076) were administered via intramuscular injection combined with electroporation (EP) for in vivo expression. All evaluable participants showed sustained antibody expression over 72 weeks without generating anti-drug antibodies (ADA). The article is well-structured and logically coherent, presenting significant potential for clinical translation.
Background Knowledge
With the continuous emergence of SARS-CoV-2 variants, traditional mRNA vaccines and neutralizing antibody therapies face limitations in certain populations. Although monoclonal antibody (mAb) therapies have been widely used for passive immunization, they still encounter challenges in production, transportation, and half-life. DNA-encoded monoclonal antibody technology offers a promising alternative that does not require continuous cold-chain storage and enables long-term in vivo expression. This study builds upon previously established tixagevimab/cilgavimab neutralizing antibodies, optimizing their DNA-encoded versions through synthetic design and delivering them using the CELLECTRA electroporation system. While animal models have demonstrated the efficiency and specificity of this platform, this human trial is the first of its kind, laying the foundation for future long-acting antibody therapies. It bridges a critical gap in mAb delivery technologies for human applications and holds significant translational medicine value.
Research Methods and Experiments
This was a phase 1, open-label, single-center, dose-escalation clinical trial involving 44 healthy adults (aged 18–60 years, BMI 20–30 kg/m²). All participants received up to four intramuscular injections of synthetic DNA plasmids (pDNA) encoding two neutralizing antibodies, AZD5396 and AZD8076, with enhanced expression achieved through the CELLECTRA electroporation system. Pharmacokinetics (PK) and safety were the primary endpoints, while exploratory endpoints included antibody binding capacity, pseudovirus neutralization activity, and ADA detection. The dose-escalation regimen included single-, double-, and quadruple-dose injections, with slight variations in injection doses and electroporation parameters across different groups to evaluate their impact on expression levels.
Key Conclusions and Perspectives
Research Significance and Prospects
This study marks the first human validation of the DNA-encoded monoclonal antibody platform, supporting its potential as a long-acting, scalable, and cold-chain-free antibody therapy. Future research should expand to larger and multi-center trials to assess its protective efficacy in real-world infections or high-risk populations. Further optimization of the platform can enhance expression levels, while exploration of its application in other infectious or autoimmune diseases can broaden its utility.
Conclusion
This study demonstrates, for the first time in humans, the feasibility and safety of synthetic DNA-encoded monoclonal antibody (DMAb) technology. All evaluable participants showed stable expression of AZD5396 and AZD8076 over 72 weeks with no anti-drug antibody response. The platform provides a promising cold-chain-free and long-term alternative for antibody therapy with substantial translational potential. Future studies should focus on expression efficiency across diverse populations, delivery method optimization, and application in other disease indications.
