Prophylactic and postexposure efficacy of a potent human monoclonal antibody against MERS coronavirus

Abstract

Middle East Respiratory Syndrome (MERS) is a highly lethal pulmonary infection caused by a previously unidentified coronavirus (CoV), likely transmitted to humans by infected camels. There is no licensed vaccine or antiviral for MERS, therefore new prophylactic and therapeutic strategies to combat human infections are needed. In this study, we describe, for the first time, to our knowledge, the isolation of a potent MERS-CoV-neutralizing antibody from memory B cells of an infected individual. The antibody, named LCA60, binds to a novel site on the spike protein and potently neutralizes infection of multiple MERS-CoV isolates by interfering with the binding to the cellular receptor CD26. Importantly, using mice transduced with adenovirus expressing human CD26 and infected with MERS-CoV, we show that LCA60 can effectively protect in both prophylactic and postexposure settings. This antibody can be used for prophylaxis, for postexposure prophylaxis of individuals at risk, or for the treatment of human cases of MERS-CoV infection. The fact that it took only 4 mo from the initial screening of B cells derived from a convalescent patient for the development of a stable chinese hamster ovary (CHO) cell line producing neutralizing antibodies at more than 5 g/L provides an example of a rapid pathway toward the generation of effective antiviral therapies against emerging viruses.MERS-CoV | neutralizing antibody | serotherapy | emerging viruses

Single-dose treatment with a humanized neutralizing antibody affords full protection of a human transgenic mouse model from lethal Middle East respiratory syndrome (MERS)-coronavirus infection

“…The MERS-CoV RBD can elicit strong neutralizing antibody response and contains a critical neutralizing domain (Ma et al, 2014; Zhang et al, 2016), thus representing an ideal target for neutralizing mAb development. Notably, almost all reported MERS-CoV neutralizing mAbs including murine, human, and humanized mAbs, target the RBD (Corti et al, 2015; Du et al, 2014; Jiang et al, 2014; Li et al, 2015; Pascal et al, 2015; Tang et al., 2014; Ying et al, 2014; Yu et al, 2015). We previously developed an RBD-targeting murine neutralizing mAb, Mersmab1, and demonstrated its ability to neutralize MERS-CoV infection (Du et al, 2014).…”

“…Several neutralizing mAbs including LCA60, REGN3051, REGN3048, 4C2h, and m336 have been tested in vivo for their protective efficacy using non-lethal MERS-CoV challenge mouse or rabbit models (Corti et al, 2015; Li et al, 2015; Pascal et al, 2015; Houser et al, 2016). In this study, we evaluated the protective efficacy of hMS-1 in a lethal hDPP4-Tg mouse model, wherein we demonstrated that a single-dose (2 mg/kg) of hMS-1 completely protected hDPP4-Tg mice from a lethal challenge from MERS-CoV.…”

“…In comparison, passive therapeutics based on neutralizing monoclonal antibodies (mAbs) has emerged as a powerful tool to provide prophylactic and therapeutic protection against viral infection (Du et al, 2013a; Zhu et al, 2013). Several human or humanized viral-neutralizing mAbs have been developed, almost all of which target the RBD (Corti et al, 2015; Jiang et al, 2014; Li et al, 2015; Pascal et al, 2015; Tang et al, 2014; Ying et al, 2014; Yu et al, 2015), further suggesting that MERS-CoV RBD represents an ideal target for neutralizing mAb development.…”

Emerging infectious diseases: MERS-COV, the new Betacoronavirus pandemic

“…While others, in an effort to develop a vaccine, involves extracting antibodies from a MERS-CoV survivor or seropositive camels. 40 However, these antibodies need time and investment, as they still to be evaluated in animal models.…”

Technical Considerations for the Generation of Novel Pseudotyped Viruses

“…The use of PVs has been of crucial significance in the rapid pace of research into the Middle Eastern Respiratory syndrome (MERS) outbreak [8][9][10][11]. During the recent Ebola outbreak, PVs were successfully used in high-throughput screening studies that helped in the identification of potential antivirals and filovirus entry inhibitors [12][13][14] as well as in the study of the viral life cycle and virus receptor interaction [15].…”