Bridging the Clinical Gap for DNA-Based Antibody Therapy Through Translational Studies in Sheep

Human Gene Therapy
Kevin HollevoetPaul Declerck

Abstract

Clinical translation of DNA-based administration of monoclonal antibodies (mAbs) is uncertain due to lack of large animal data. To bridge the clinical gap, we evaluated a panel of novel plasmid DNA (pDNA)-encoded mAbs in 40-70 kg sheep with a clinical intramuscular electroporation protocol. Injection of 4.8 mg of pDNA, encoding ovine anti-human CEA mAb (OVAC), led to peak plasma mAb titers of 300 ng/mL. OVAC remained detectable for 3 months and was boosted by a second pOVAC administration. Hyaluronidase muscle pretreatment increased OVAC concentrations up to 10-fold. These higher plasma titers, however, led to anti-drug antibodies (ADAs) toward the OVAC variable regions, resulting in loss of mAb detection and of adequate redosing. Transient immune suppression avoided ADA formation, with OVAC peaking at 3.5 μg/mL and remaining detectable for 11 months after pOVAC injection. DNA-based delivery of ovine anti-human EGFR mAb (OVAE), identical to OVAC except for the variable regions, preceded by hyaluronidase, allowed for at least three consecutive administrations in an immune-competent sheep, without ADA response. When tripling the pOVAE dose to 15 mg, transient ADAs of limited impact were observed; plasma OVAE peaked at 2.6 μg/mL a...Continue Reading

References

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Citations

Jun 25, 2020·Emerging Microbes & Infections·Chasity D AndrewsRachel A Liberatore
Mar 12, 2020·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Ami PatelDavid B Weiner
Feb 27, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Liesl JacobsKevin Hollevoet

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Methods Mentioned

BETA
electrophoresis
enzyme-linked
Transfection
ELISA
affinity capture elution
ELISAs

Clinical Trials Mentioned

NCT01138410
NCT03831503

Software Mentioned

pOVAC
GraphPad
GraphPad Prism

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