Stable antibody expression at therapeutic levels using the 2A peptide

Area of Science:

• Biotechnology
• Gene Therapy
• Immunology

Background:

• Therapeutic monoclonal antibodies (mAbs) show promise for treating cancer and other diseases.
• Manufacturing limitations may hinder the widespread clinical application of mAb therapies.

Purpose of the Study:

• To develop a gene therapy system for continuous in vivo production of full-length therapeutic mAbs.
• To assess the feasibility and efficacy of a recombinant adeno-associated virus (rAAV) vector delivering an anti-VEGFR2 mAb.

Main Methods:

• Constructed a single open reading frame expression system linking mAb heavy and light chains via a 2A self-processing peptide.
• Generated a recombinant adeno-associated virus serotype 8 (rAAV8) vector encoding the VEGFR2-neutralizing mAb DC101 (rAAV8-DC101).
• Administered a single dose of rAAV8-DC101 to mice to evaluate in vivo antibody expression and anti-tumor efficacy.

Main Results:

• Achieved long-term expression of therapeutic mAb DC101 at concentrations exceeding 1,000 microg/ml in mice following a single rAAV8-DC101 dose.
• Demonstrated significant anti-tumor efficacy in vivo, confirming the therapeutic potential of the gene-delivered mAb.
• Validated the gene therapy approach for stable, high-level delivery of mAbs.

Conclusions:

• This study presents the first feasible gene therapy approach for sustained in vivo delivery of therapeutic monoclonal antibodies.
• The developed system offers a promising alternative to conventional mAb administration, potentially overcoming manufacturing and delivery challenges.
• Continuous, high-concentration mAb production via gene transfer may expand therapeutic options for various diseases.