In Vivo Delivery of Synthetic Human DNA-Encoded Monoclonal Antibodies Protect against Ebolavirus Infection in a Mouse Model

Patel, Ami; Park, Daniel H.; Davis, Carl W.; Smith, Trevor R.F.; Leung, Anders; Tierney, Kevin; Bryan, Aubrey L.; Davidson, Edgar; Yu, Xiaoying; Racine, Trina; Reed, Charles C.; Gorman, Marguerite E.; Wise, Megan C.; Elliott, Sarah T. C.; Esquivel, Rianne N.; Yan, Jian; Chen, Jing; Muthumani, Kar; Doranz, Benjamin J.; Saphire, Erica Ollmann; Crowe, James E.; Broderick, Kate E.; Kobinger, Gary P.; He, Shihua; Qiu, Xiangguo; Kobasa, Darwyn; Humeau, Laurent; Sardesai, Niranjan Y.; Ahmed, Rafi; Weiner, David B.

doi:10.1016/j.celrep.2018.10.062

Cited by 39 publications

(72 citation statements)

References 53 publications

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“…4c ). To assess levels and durability of in vivo expression, mice were conditioned to reduce the T cell compartment using CD4 and CD8-depleting antibodies, this has been shown to permit the expression of a human mAb construct in mice in the absence of a host anti-drug antibody (ADA) response 25 . Administration of dMAb 2-12C pDNA to the tibialis anterior muscle was associated an increased durability of circulating levels of the mAb in the serum compared to rec 2-12C, administered intravenously ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Establishment of a pig influenza challenge model for evaluation of monoclonal antibody delivery platforms

McNee

Smith

Holzer

et al. 2020

Preprint

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31Monoclonal antibodies are a possible adjunct to vaccination and drugs in treatment of 32 influenza virus infection. However questions remain whether small animal models 33 accurately predict efficacy in humans. We have established the pig, a large natural 34 host animal for influenza, with many physiological similarities to humans, as a robust 35 model for testing monoclonal antibodies. We show that a strongly neutralizing 36 monoclonal antibody (2-12C) against the hemagglutinin head administered 37prophylactically at 15 mg/kg reduced viral load and lung pathology after pandemic 38 H1N1 influenza challenge. A lower dose of 1 mg/kg of 2-12C or a DNA plasmid 39 encoded version of 2-12C, reduced pathology and viral load in the lungs, but not viral 40 shedding in nasal swabs. We propose that the pig influenza model will be useful for 41 testing candidate monoclonal antibodies and emerging delivery platforms prior to 42 human trials. 43 therapeutic administration to reduce viral load after infection has been established. 94We went on to evaluate the potential of an in vivo produced 2-12C using synthetic 95 dMAb technology in support of the translation of this technology to humans as an 96 immunoprophylactic. 97 98 Results: 99Establishment of a prophylactic pig influenza challenge model with recombinant 100 2-12C mAb. To establish a positive control protective mAb and delivery method in the 101 pig influenza model we tested the strongly neutralizing human IgG1 anti-head 2-12C 102 mAb 31 in a prophylactic experiment. We administered 15 mg/kg of 2-12C intravenously 103 and the control groups received an isotype matched IgG1 mAb or the diluent. Twenty-104 four hours later the pigs were challenged with pandemic swine H1N1 isolate, 105 A/swine/England/1353/2009 (pH1N1) and 4 days later culled to assess viral load and 106 pathology (Fig. 1a). 2-12C significantly decreased viral load in nasals swabs on each 107 day over the course of infection, although the decrease was less on days 2 and 3 than 108 days 1 and 4 (Fig. 1b). The total viral load in nasal swabs over the 4 days in animals 109 treated with 2-12C was also significantly less as determined by the area under the 110 curve (AUC) compared to diluent and isotype controls (p=0.0267 and p=0.021). Viral 111 load in the 2-12C group was significantly reduced in the BAL and no virus was detected 112 in the lungs at 4 days post infection (DPI). Overall 2-12C had a clear effect on viral 113 load in nasal swabs, BAL and lung. 114The isotype and diluent control groups showed the most severe gross 115 pathology and histopathology scores (Fig. 2a). The red tan areas of pulmonary 116 consolidation were present mainly in the cranial and middle lung lobes of animals from 117 the isotype and diluent groups, but no lesions were found in the 2-12C group (Fig. 2b). 118 6 Similarly, necrotizing bronchiolitis and bronchial and alveolar exudation, and mild 119 thickening of the alveolar septa was shown in the animals from both control groups. 120

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Section: Resultsmentioning

confidence: 99%

Establishment of a pig influenza challenge model for evaluation of monoclonal antibody delivery platforms

McNee

Smith

Holzer

et al. 2020

Preprint

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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%

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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“…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

140

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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In Vivo Delivery of Synthetic Human DNA-Encoded Monoclonal Antibodies Protect against Ebolavirus Infection in a Mouse Model

Cited by 39 publications

References 53 publications

Establishment of a pig influenza challenge model for evaluation of monoclonal antibody delivery platforms

Establishment of a pig influenza challenge model for evaluation of monoclonal antibody delivery platforms

In Vivo Delivery of Nucleic Acid-Encoded Monoclonal Antibodies

DNA vaccines: prime time is now

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