TY - JOUR
T1 - Intramuscular Delivery of Replicon RNA Encoding ZIKV-117 Human Monoclonal Antibody Protects against Zika Virus Infection
AU - Erasmus, Jesse H.
AU - Archer, Jacob
AU - Fuerte-Stone, Jasmine
AU - Khandhar, Amit P.
AU - Voigt, Emily
AU - Granger, Brian
AU - Bombardi, Robin G.
AU - Govero, Jennifer
AU - Tan, Qing
AU - Durnell, Lorellin A.
AU - Coler, Rhea N.
AU - Diamond, Michael S.
AU - Crowe, James E.
AU - Reed, Steven G.
AU - Thackray, Larissa B.
AU - Carnahan, Robert H.
AU - Van Hoeven, Neal
N1 - Publisher Copyright:
© 2020 The Author(s)
PY - 2020/9/11
Y1 - 2020/9/11
N2 - Monoclonal antibody (mAb) therapeutics are an effective modality for the treatment of infectious, autoimmune, and cancer-related diseases. However, the discovery, development, and manufacturing processes are complex, resource-consuming activities that preclude the rapid deployment of mAbs in outbreaks of emerging infectious diseases. Given recent advances in nucleic acid delivery technology, it is now possible to deliver exogenous mRNA encoding mAbs for in situ expression following intravenous (i.v.) infusion of lipid nanoparticle-encapsulated mRNA. However, the requirement for i.v. administration limits the application to settings where infusion is an option, increasing the cost of treatment. As an alternative strategy, and to enable intramuscular (IM) administration of mRNA-encoded mAbs, we describe a nanostructured lipid carrier for delivery of an alphavirus replicon encoding a previously described highly neutralizing human mAb, ZIKV-117. Using a lethal Zika virus challenge model in mice, our studies show robust protection following alphavirus-driven expression of ZIKV-117 mRNA when given by IM administration as pre-exposure prophylaxis or post-exposure therapy.
AB - Monoclonal antibody (mAb) therapeutics are an effective modality for the treatment of infectious, autoimmune, and cancer-related diseases. However, the discovery, development, and manufacturing processes are complex, resource-consuming activities that preclude the rapid deployment of mAbs in outbreaks of emerging infectious diseases. Given recent advances in nucleic acid delivery technology, it is now possible to deliver exogenous mRNA encoding mAbs for in situ expression following intravenous (i.v.) infusion of lipid nanoparticle-encapsulated mRNA. However, the requirement for i.v. administration limits the application to settings where infusion is an option, increasing the cost of treatment. As an alternative strategy, and to enable intramuscular (IM) administration of mRNA-encoded mAbs, we describe a nanostructured lipid carrier for delivery of an alphavirus replicon encoding a previously described highly neutralizing human mAb, ZIKV-117. Using a lethal Zika virus challenge model in mice, our studies show robust protection following alphavirus-driven expression of ZIKV-117 mRNA when given by IM administration as pre-exposure prophylaxis or post-exposure therapy.
KW - Gene-encoded antibody
KW - RNA delivery
KW - RNA therapeutic
KW - antibody delivery
KW - monoclonal antibody
KW - replicon
KW - self-amplifying RNA
UR - http://www.scopus.com/inward/record.url?scp=85087743965&partnerID=8YFLogxK
U2 - 10.1016/j.omtm.2020.06.011
DO - 10.1016/j.omtm.2020.06.011
M3 - Article
C2 - 32695842
AN - SCOPUS:85087743965
SN - 2329-0501
VL - 18
SP - 402
EP - 414
JO - Molecular Therapy - Methods and Clinical Development
JF - Molecular Therapy - Methods and Clinical Development
ER -