In Vivo Delivery of Nucleic Acid-Encoded Monoclonal Antibodies

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. Key PointsDirect 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 pDNA-mAbs, 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.

Safe and effective aerosolization of in vitro transcribed mRNA to the respiratory tract epithelium of horses without a transfection agent

“…Typically IVT mRNA therapeutics are delivered systematically by intravenous (IV) administration 3 – 6 , 8 . This approach is not the most effective when a local therapeutic application is needed, and often requires large doses 4 , 5 .…”

“…However, this large contact area of the lungs can also be used as an effective entry point for the administration of mRNA by nebulization that can then be translated into proteins for local action 24 . To prevent immune activation and inflammation in the lung, we used highly purified codon-optimized IVT mRNA, which was made with 5-methoxyuridine instead of uridine 4 , 5 , 19 . Moreover, limiting any innate immune activation also increases the efficiency of protein translation 33 , 34 .…”

“…Recent technological innovations have enabled IVT mRNA to become a promising therapeutic tool with numerous medical applications [3][4][5][6][7][8][9] . The production and purification process of IVT mRNA can easily be standardized, thereby avoiding the need for costly product-specific production and purification steps.…”

“…Since the original reports of the first successful translation of IVT mRNA in mice 13 , 14 , much progress has been made to improve translation efficiency and overcome problems of stability. We now better understand the innate inflammatory responses to IVT mRNA, such that it can be avoided by using optimized codons and modified uracil nucleosides, and increasing the product purity 3 – 5 , 15 , 16 . Notwithstanding that naked mRNA (i.e., mRNA delivered without a delivery vehicle) has been applied in several in vivo studies, it has become dogma that efficient carriers (so-called transfection agents) are needed to substantially enhance mRNA stability and transfection efficiency 17 , 18 .…”

In vivo expressed biologics for infectious disease prophylaxis: rapid delivery of DNA-based antiviral antibodies

“…Regardless of the delivery system, the goal of all nucleic acid-based mAb platforms is expression and production of the mAb by the target cells (e.g. skeletal muscle cells or hepatocytes, depending on the route of administration), resulting in secretion of mAbs and eventual uptake by the vascular system [32].…”