In vivo delivery of synthetic DNA–encoded antibodies induces broad HIV-1–neutralizing activity

Wise, Megan C.; Xu, Ziyang; Tello‐Ruiz, Edgar; Beck, Charles; Trautz, Aspen; Patel, Ami; Elliott, Sarah T. C.; Chokkalingam, Neethu; Kim, Sophie; Kerkau, Melissa; Muthumani, Kar; Jiang, Jingjing; Fisher, Paul D.; Ramos, Stephanie; Smith, Trevor R.F.; Mendoza, Janess; Broderick, Kate E.; Montefiori, David C.; Ferrari, Guido; Kulp, Daniel W.; Humeau, Laurent; Weiner, David B.

doi:10.1172/jci132779

Cited by 39 publications

(48 citation statements)

References 47 publications

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“…The literature describes that pDNA-mAbs can exhibit peak serum concentrations after just 2 weeks and then can express at consistent levels for 2-3 months and decline thereafter as the plasmid is lost from cells and then cleared from the serum due to the natural half-life of immunoglobulin G (IgG) [36][37][38][39][40][41]. Long-term small animal studies show the total duration of pDNA-mAb expression to be at least 1 year [42,43]. However, in contrast to viral vectors, synthetic DNA requires an efficient delivery system.…”

Section: Synthetic Dnamentioning

confidence: 99%

“…A recent study by Schommer et al utilizing chondroitinase ABC to degrade chondroitin, also present in the ECM, describes this enzyme as an alternative to hyaluronidase [99]. More recent studies have addressed the need for hyaluronidase pre-treatment and are utilizing co-formulation with recombinant human hyaluronidase (Hylenex ® ) in non-human primates [43]. The Zika DMAb phase I trial is utilizing this co-formulated approach.…”

Section: In Vivo Synthetic Dna Deliverymentioning

confidence: 99%

“…Patel et al introduced single amino acid modifications into the Fab framework region to optimize DMAb-4G7 to restore in vivo expression [42]. Similar modifications were introduced into the framework of an anti-CTLA4 DMAb [100] and anti-HIV DMAbs [43] to achieve highly optimized in vivo expression [100]. Therefore, sequence optimizations have clearly played a critical role in in vivo expression of synthetic pDNA-mAbs.…”

Section: Sequence Optimizationsmentioning

confidence: 99%

“…[126]). Wise et al engineered a panel of 16 broadly neutralizing HIV-1 antibodies as DMAbs and delivered them in mice and non-human primates [43]. The DMAbs, delivered alone or in combination, demonstrated long expression for 300 days and neutralized against the global panel viruses in an in vitro neutralization assay.…”

Section: Anti-hiv Pdna-mabsmentioning

confidence: 99%

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In Vivo Delivery of Nucleic Acid-Encoded Monoclonal Antibodies

2020

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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.

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Section: Synthetic Dnamentioning

confidence: 99%

Section: In Vivo Synthetic Dna Deliverymentioning

confidence: 99%

Section: Sequence Optimizationsmentioning

confidence: 99%

Section: Anti-hiv Pdna-mabsmentioning

confidence: 99%

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In Vivo Delivery of Nucleic Acid-Encoded Monoclonal Antibodies

2020

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“…Early reports described the use of plasmid vector systems for the generation of antibody like molecules as well as anti-HIV-1 envelope neutralizing F(ab)s [31]. Xu et al reported Synthetic DNA vaccines: prime time is approaching Gary and Weiner 25 [33 ]. This platform continues to advance and DMAbs targeting influenza A and B [34,35], dengue [36], Chikungunya [37 ], Zika [38 ], and Ebola [35,39] with of protection in animal models.…”

Section: Syndna Biologics In the Preclinical Settingmentioning

confidence: 99%

DNA vaccines: prime time is now

Gary

Weiner

2020

Current Opinion in Immunology

148

118

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Recently newer synthetic DNA vaccines have been rapidly advanced to clinical study and have demonstrated an impressive degree of immune potency and tolerability. Improvements in DNA delivery over prior needle and syringe approaches include jet delivery, gene gun delivery, among others. Among the most effective of these new delivery methods, advanced electroporation (EP), combined with other advances, induces robust humoral and cellular immunity in both preventative as well as therapeutic studies. Advancements in the design of the DNA inserts include leader sequence changes, RNA and codon optimizations, improved insert designs, increased concentrations of DNA, and skin delivery, appear to complement newer delivery strategies. These advances also provide a framework for the in vivo production of synthetic DNA biologics. In this review, we focus on recent studies of synthetic DNA vaccines in the clinic for the prevention or treatment of infectious diseases with a focus on adaptive electroporation for delivery, and briefly summarize novel preclinical data advancing the in vivo delivery of DNAencoded antibody-like biologics.

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Techniques for Developing and Assessing Immune Responses Induced by Synthetic DNA Vaccines for Emerging Infectious Diseases

Bordoloi

et al. 2021

Vaccine Design

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Vaccines are one of mankind's greatest medical advances, and their use has drastically reduced and in some cases eliminated (e.g., smallpox) disease and death caused by infectious agents. Traditional vaccine modalities including live-attenuated pathogen vaccines, wholly inactivated pathogen vaccines, and proteinbased pathogen subunit vaccines have successfully been used to create efficacious vaccines against measles, mumps, rubella, polio, and yellow fever. These traditional vaccine modalities, however, take many months to years to develop and have thus proven less effective for use in creating vaccines to emerging or reemerging infectious diseases (EIDs) including influenza, Human immunodeficiency virus (HIV), dengue virus (DENV), chikungunya virus (CHIKV), West Nile virus (WNV), Middle East respiratory syndrome (MERS), and the severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV and SARS-CoV-2). As factors such as climate change and increased globalization continue to increase the pace of EID development, newer vaccine modalities are required to develop vaccines that can prevent or attenuate EID outbreaks throughout the world. One such modality, DNA vaccines, has been studied for over 30 years and has numerous qualities that make them ideal for meeting the challenge of EIDs including; (1) DNA vaccine candidates can be designed within hours of publishing of a pathogens genetic sequence; (2) they can be manufactured cheaply and rapidly in large quantities; (3) they are thermostable and have reduced requirement for a cold-chain during distribution, and (4) they have a remarkable safety record in the clinic. Optimizations made in plasmid design as well as in DNA vaccine delivery have greatly improved the immunogenicity of these vaccines. Here we describe the process of making a DNA vaccine to an EID pathogen and describe methods used for assessing the immunogenicity and protective efficacy of DNA vaccines in small animal models.

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In vivo delivery of synthetic DNA–encoded antibodies induces broad HIV-1–neutralizing activity

Cited by 39 publications

References 47 publications

In Vivo Delivery of Nucleic Acid-Encoded Monoclonal Antibodies

In Vivo Delivery of Nucleic Acid-Encoded Monoclonal Antibodies

DNA vaccines: prime time is now

Techniques for Developing and Assessing Immune Responses Induced by Synthetic DNA Vaccines for Emerging Infectious Diseases

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