Abstract
Antibody immunotherapy is revolutionizing modern medicine. The field has advanced dramatically over the past 40 years, driven in part by major advances in isolation and manufacturing technologies that have brought these important biologics to the forefront of modern medicine. However, the global uptake of monoclonal antibody (mAb) biologics is impeded by biophysical and biochemical liabilities, production limitations, the need for cold-chain storage and transport, as well as high costs of manufacturing and distribution. Some of these hurdles may be overcome through transient in vivo gene delivery platforms, such as non-viral synthetic plasmid DNA and messenger RNA vectors that are engineered to encode optimized mAb genes. These approaches turn the body into a biological factory for antibody production, eliminating many of the steps involved in bioprocesses and providing several other significant advantages, and differ from traditional gene therapy (permanent delivery) approaches. In this review, we focus on nucleic acid delivery of antibody employing synthetic plasmid DNA vector platforms, and RNA delivery, these being important approaches that are advancing simple, rapid, in vivo expression and having an impact in animal models of infectious diseases and cancer, among others.
Highlights
Delivery by specific lipid nanoparticle (LNP) has significantly reduced recognition of messenger RNA (mRNA) by innate sensors; mRNA must exit the LNP into the cytoplasm in order to be translated, and still encounters sensors. This results in recognition by innate pattern recognition receptors such as toll-like receptors TLR3, TLR7, TLR8, and TLR9 that respond to mRNA by inducing inflammatory responses via endosomal compartments and retinoic acid-inducible genelike receptors (RLRs), RIG-I, MDA5, and LGP2, that recognize unmethylated CpG nucleotides and single-stranded RNA to initiate degradation [50, 51]
Their study showed expression for this DNA-encoded mAb (DMAb) delivery of over 105 days post-injection, with important anti-tumor functionality, as tumor-challenged mice exhibited tumor regression and greater than 80% survival 58 days post-challenge compared to 0% survival in the vector control mice
natural killer (NK)-cell-depleted mice injected with anti-PSMA DMAb and challenged were significantly less able to clear tumor and had less than 10% viability after a 56-day challenge compared to NKexpressing mice
Summary
Direct in vivo delivery of synthetic nucleic acidencoded antibodies employing plasmid DNA [plasmid DNA-encoded monoclonal antibodies (pDNA-mAbs)] and messenger RNA-encoded monoclonal antibodies (mRNA-mAbs) platforms represent new approaches for the in vivo delivery of antibody-like biologics. While there are more preclinical data using pDNAmAbs, both platforms have made significant progress and are demonstrating promising efficacy in infectious disease and cancer studies in small and large animal models. These platforms have advantages such as rapid product development and simpler manufacturing processes, yet they represent different strategies for deployment, with unique advantages and challenges
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