Rapid In Vivo Screening of Monoclonal Antibody Cocktails: A Game Changer in Therapeutic Development
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In a groundbreaking study, Fausther-Bovendo et al. have developed a novel, rapid, and cost-effective method for screening therapeutic monoclonal antibody (mAb) candidates and cocktails directly in living systems. This advancement holds significant promise for accelerating the fight against emerging and rapidly mutating pathogens, as well as for applications in cancer and autoimmune diseases.

Key Findings from the Paper

The traditional pipeline for mAb development faces significant bottlenecks, particularly in the rapid selection and production of sufficient quantities of mAb candidates for preclinical in vivo studies. This research addresses this challenge by introducing the hydrodynamic delivery (HD) of DNA-encoded modified antibodies (DNA-scFv-IgG).

The study's key findings include:

  • Transformation of mAbs into scFv-IgG: Four conventional mAbs targeting respiratory syncytial virus (RSV), human metapneumovirus (HMPV), severe acute respiratory syndrome virus (SARS), and SARS-CoV-2 were successfully converted into single-chain variable fragments fused to the fragment crystallizable (Fc) region of a human IgG1 (scFv-IgG). This modification prevents the formation of non-functional mAbs with improper heavy and light chain pairing when administered as a cocktail.
  • High Expression In Vitro and In Vivo: The DNA-scFv-IgG constructs demonstrated high expression both in vitro (in HEK293 cells) and in vivo (in mice) following transfection or hydrodynamic delivery. This high expression is crucial for effective therapeutic screening.
  • Protection in Murine Infection Models: The method successfully provided protection in two different murine infection models: SARS-CoV-2 and RSV. This in vivo validation highlights the therapeutic potential of the DNA-scFv-IgG approach.
  • Rapid and Low-Cost Screening: By utilizing naked plasmid DNA, which is easily produced and highly stable, the new method significantly reduces the cost and time associated with traditional mAb production, making in vivo screening much more efficient.
  • Suitability for Cocktail Screening: The platform allows for the rapid screening of both individual mAb candidates and mAb cocktails in mouse models, which is essential for developing comprehensive therapeutic strategies against complex pathogens or diseases.

Role of ichorbio's Antibodies

ichorbio's antibodies played a crucial role as controls in this research, demonstrating their reliability and utility in preclinical studies. The following ichorbio antibodies were used in the paper:

  • Sotrovimab: Used as a positive control in the SARS-CoV-2 challenge model.
  • Palivizumab: Used as a positive control in the RSV challenge model.

Implications and Future Directions

This study's findings have profound implications for the future of therapeutic antibody development. The ability to rapidly and affordably screen mAb candidates in vivo will accelerate the identification of effective treatments for a wide range of diseases, particularly in response to emerging infectious threats.

The rapid rise of circulating scFv-IgG levels following hydrodynamic delivery suggests that this method could be employed not only for prophylactic assessment but also for therapeutic evaluation. Furthermore, the demonstrated success with a cocktail targeting different pathogens opens avenues for developing multi-pronged approaches against single pathogens by targeting distinct viral proteins or multiple variants simultaneously.

Suggested Future Experiments

To further build upon these promising results, several future experiments are suggested:

  • Optimization for Therapeutic Use: Investigate the optimal timing and dosing of DNA-scFv-IgG hydrodynamic delivery for therapeutic intervention, rather than just prophylactic use.
  • Screening against Other Diseases: Extend the application of this platform to screen mAb candidates for cancers and autoimmune diseases, leveraging the broad applicability of mAb therapies.
  • Investigating Isotype Switching: Delve deeper into the impact of isotype switching on therapeutic efficacy within this DNA-encoded antibody framework, building on previous studies that used hydrodynamic delivery for influenza virus-specific mAbs.
  • Testing in Larger Animal Models: Explore the feasibility of using hydrodynamic limb vein (HLV) injection in larger mammal species, including non-human primates (NHPs), to screen therapeutic mAbs. This would bridge the gap between rodent studies and human clinical trials.
  • Correlation of Expression with Efficacy: Further characterize the relationship between the in vitro and in vivo production yield of scFv-IgGs and their therapeutic efficacy to better predict lead candidates.

Conclusion

The development of a rapid, low-cost in vivo screening method for monoclonal antibody candidates and cocktails using hydrodynamic delivery of DNA-encoded modified antibodies represents a significant leap forward in biomedicine. This innovative platform has the potential to dramatically expedite the discovery and validation of new antibody-based therapies, ultimately leading to more timely and effective interventions against a myriad of diseases. By streamlining the early stages of mAb development, researchers can focus cumbersome manufacturing processes only on the most promising lead candidates, transforming the landscape of antibody therapeutics.

 

Reference

Fausther-Bovendo H, Babuadze G, Ivanciuc T, Kalveram B, Qu Y, Choi J, McGeer A, Ostrowski M, Mubareka S, Patel A, et al. Rapid In Vivo Screening of Monoclonal Antibody Cocktails Using Hydrodynamic Delivery of DNA-Encoded Modified Antibodies. Biomedicines. 2025; 13(3):637. https://doi.org/10.3390/biomedicines13030637