Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection

Abstract

Traditional approaches to antimicrobial drug development are poorly suited to combatting the emergence of novel pathogens. Additionally, the lack of small animal models for these infections hinders the in vivo testing of potential therapeutics. Here we demonstrate the use of the VelocImmune technology (a mouse that expresses human antibody-variable heavy chains and κ light chains) alongside the VelociGene technology (which allows for rapid engineering of the mouse genome) to quickly develop and evaluate antibodies against an emerging viral disease. Specifically, we show the rapid generation of fully human neutralizing antibodies against the recently emerged Middle East Respiratory Syndrome coronavirus (MERS-CoV) and development of a humanized mouse model for MERS-CoV infection, which was used to demonstrate the therapeutic efficacy of the isolated antibodies. The VelocImmune and VelociGene technologies are powerful platforms that can be used to rapidly respond to emerging epidemics.

CD8 + T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome

“…Endogenous DPP4 expression is not restricted to the lungs and also has a distinct tissue distribution, with some organs expressing higher levels than others (reviewed in reference 24). By maintaining the mDPP4 gene promoter and the 3= untranslated region (UTR) to control hDPP4 (27), we aimed to achieve a model in which hDPP4 matched the tissue distribution and expression levels observed for endogenous mDPP4. To test this, we compared hDPP4 mRNA expression to mDPP4 mRNA expression in a range of organs and in blood.…”

“…This limited-duration study, up to 4 days postinfection, did not demonstrate significant clinical signs of MERS-CoV infection, e.g., weight loss (27). In this study, we describe and characterize this novel mouse model for MERS-CoV infection in more detail.…”

Mapping the Specific Amino Acid Residues That Make Hamster DPP4 Functional as a Receptor for Middle East Respiratory Syndrome Coronavirus

“…Nonhuman primates (NHPs) (2-4) and dromedary camels (5) are naturally susceptible. In addition, several mouse models have been developed, and expression of the human variant of the receptor of MERS-CoV, dipeptidyl peptidase 4 (DPP4), in mice allows viral replication (6)(7)(8).No other small-animal models have been developed. Therefore, if a treatment against MERS-CoV is shown to be successful in the mouse model, further characterization of the treatment needs to be performed in NHPs, a relatively expensive animal model to which access is limited.…”

“…Nonhuman primates (NHPs) (2-4) and dromedary camels (5) are naturally susceptible. In addition, several mouse models have been developed, and expression of the human variant of the receptor of MERS-CoV, dipeptidyl peptidase 4 (DPP4), in mice allows viral replication (6)(7)(8).…”

Review on Middle East Respiratory Syndrome

“…Monoclonal antibodies that efficiently block the interaction between the MERSCoV envelope spike glycoprotein and a human protein dipeptidyl peptidase 4 have been developed using a humanized mouse (transgenic mouse). These researchers are now working to move the antibodies into human trials [41]. Based on experience with SARS-CoV, the use of convalescent plasma, hyper-immune globulin, or human monoclonal antibodies that contain neutralizing antibodies may be efficacious and is recommended as first-line treatment when available [40].…”