DNA-encoded bispecific T cell engagers and antibodies present long-term antitumor activity

Perales‐Puchalt, Alfredo; Duperret, Elizabeth K.; Yang, Xue; Hernández, Patricia; Wojtak, Krzysztof; Zhu, Xizhou; Jung, Seang-Hwan; Tello‐Ruiz, Edgar; Wise, Megan C.; Montaner, Luis J.; Muthumani, Kar; Weiner, David B.

doi:10.1172/jci.insight.126086

Cited by 36 publications

(44 citation statements)

References 21 publications

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“…Alternative in vivo antibody gene transfer strategies using DNA, RNA or viral vectors have shown that antibody genes can be stably maintained in the host tissue, resulting in potent and long-term expression of mAbs in the body following a single administration 17–23 . DNA plasmid encoded mAbs (dMAbs), which are delivered to muscle tissue, are a novel approach with the potential to provide durable immunity 24–26 . The plasmid DNA is well-tolerated and nonintegrating, does not require cold-chain distribution, can be delivered repeatedly and is relatively inexpensive to produce.…”

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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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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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“…Therefore, a plasmid-encoded delivered BiTE would undoubtedly improve upon the relative short expression time length and could significantly lower the cost of such an important treatment. Building on previous DMAb studies, Perales-Puchalt et al engineered a DNA-encoded bispecific T-cell engager (DBTE) that binds to CD3 T cells and the Her2 tumor target [119]. This study demonstrated consistent in vivo expression and cytotoxic activity for approximately 4 months, with potent functional activity showing 8/10 tumor regression/ clearance in mice > 40 days after tumor challenge.…”

Section: Cancer: Outlookmentioning

confidence: 88%

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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“…Our novel synthetic vaccine was subjected to combined enhancements of plasmid antigen design including codon optimization, RNA optimization, RNA stabilization and increased leader sequence utilization which are favorable over traditional vaccines owing to their safety, cost-effectiveness and ability to modulate immune responses against POWV to increase the chances of protection [ 21 , 22 , 24 , 26 , 29 , 33 ]. Priming of mice with POWV-SEV was done by intramuscular injection followed by electroporation resulting in strong cellular and humoral immune responses measured by T cell ELISpot and ELISA assays.…”

Section: Discussionmentioning

confidence: 99%

A novel synthetic DNA vaccine elicits protective immune responses against Powassan virus

Choi¹,

Kudchodkar²,

Ho³

et al. 2020

PLoS Negl Trop Dis

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Powassan virus (POWV) infection is a tick-borne emerging infectious disease in the United States and North America. Like Zika virus, POWV is a member of the family Flaviviridae. POWV causes severe neurological sequalae, meningitis, encephalitis, and can cause death. Although the risk of human POWV infection is low, its incidence in the U.S. in the past 16 years has increased over 300%, urging immediate attention. Despite the disease severity and its growing potential for threatening larger populations, currently there are no licensed vaccines which provide protection against POWV. We developed a novel synthetic DNA vaccine termed POWV-SEV by focusing on the conserved portions of POWV pre-membrane and envelope (prMEnv) genes. A single immunization of POWV-SEV elicited broad T and B cell immunity in mice with minimal cross-reactivity against other flaviviruses. Antibody epitope mapping demonstrated a similarity between POWV-SEV-induced immune responses and those elicited naturally in POWV-infected patients. Finally, POWV-SEV induced immunity provided protection against POWV disease in lethal challenge experiments.

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DNA-encoded bispecific T cell engagers and antibodies present long-term antitumor activity

Cited by 36 publications

References 21 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

A novel synthetic DNA vaccine elicits protective immune responses against Powassan virus

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