Delivery of mRNA encoding an anti-tau monoclonal antibody and engineered scFv intrabody results in functional antibody expression in SH-SY5Y cells

Abstract

AbstractMonoclonal antibodies have emerged as a leading therapeutic agent for the treatment of disease, including Alzheimer’s disease. In the last year, two anti-amyloid monoclonal antibodies, lecanemab and aducanumab, have been approved in the USA for the treatment of Alzheimer’s disease, whilst several tau-targeting monoclonal antibodies are currently in clinical trials. Such antibodies, however, are expensive and timely to produce and require frequent dosing regimens to ensure disease-modifying effects. Syntheticin vitro-transcribed mRNA encoding antibodies for endogenous protein expression holds the potential to overcome many of the limitations associated with protein antibody production. Here, we have generated syntheticin vitro-transcribed mRNA encoding a tau specific monoclonal antibody as a full-sized IgG and as a single chain variable fragment (scFv).In vitrotransfection of human neuroblastoma SH-SY5Y cells demonstrated the ability of the synthetic mRNA to be translated into functional tau-specific antibodies. Furthermore, we show that the translation of the tau-specific scFv as an intrabody results in the specific engagement of intracellular tau. This work highlights the utility of mRNA for the delivery of antibody therapeutics, including intrabodies, for the targeting of tau in tauopathies.