Rapid generation of a human monoclonal antibody to combat Middle East respiratory syndrome

Abstract

The last century has witnessed the emergence of several previously unknown viruses as life-threatening human pathogens. Several examples include HIV, Ebola, Lujo, and, most recently, the Middle East respiratory syndrome (MERS) and Ebola. In this study, we describe a method for the swift generation of a human-derived monoclonal antibody, known as LCA60, as a treatment for MERS infections. LCA60 antibody was generated using the Cellclone Technology from the immortalized B cells of a human donor recovering from MERS. Only four months were required from the initial screening of B cells to the development of a stable CHO cell line suitable for the production of clinical grade antibody, thereby delineating a rapid pathway for the development of antiviral therapies against emerging viruses. Currently, the LCA60 antibody is being considered for clinical development, which includes prophylaxis in individuals at risk and a treatment for severe MERS-CoV infections.

MERS coronavirus outbreak: Implications for emerging viral infections

“…The S protein and its binding to DPP4 is the target of many proposed direct MERS-CoV therapies, including a large number of antibodies which target the interaction either from the viral or the host side Corti et al, 2016;Du et al, 2014;Houser et al, 2016;Jiang et al, 2014;Johnson et al, 2016;Li et al, 2015;Niu et al, 2018;Ohnuma et al, 2013;Qiu et al, 2016;Ying et al, 2014;Yu et al, 2015). Monoclonal antibodies against the RBD of the S1 region have particularly strong neutralizing capacity, although full-length S or S1 targeting antibodies may have greater potential in a vaccine context given their larger number of target epitopes and the reduced chance of escape mutations Corti et al, 2016;Du et al, 2014;Houser et al, 2016;Jiang et al, 2014;Johnson et al, 2016;Li et al, 2015;Niu et al, 2018;Ohnuma et al, 2013;Qiu et al, 2016;Ying et al, 2014;Yu et al, 2015). A fusion product in which truncated RBD (residues 377-588) was joined to the Fc portion of human IgG could bind human DPP4 and inhibit MERS-CoV infection in vitro in cell culture and in vivo in infected mice (Table 2) (Du et al, 2013).…”

“…A particularly promising antibody candidate for MERS-CoV therapy is the human antibody LCA60, as it targets both the N-terminal domain (NTD) and the RBD of S1 (Table 2) (Corti et al, 2016). LCA60 was isolated from B cells of a MERS-CoV-infected human donor, and has been used to establish a stable CHO cell line from which clinical grade antibody is reliably available (Corti et al, 2016); this type of ready availability would be of particular benefit in KSA for outbreak situations. It had both prophylactic and therapeutic activities against MERS-CoV infection in 2 transgenic mouse models, Ad5/hDPP4 and type I interferon receptor (IFNAR)-KO (Corti et al, 2016).…”

“…LCA60 was isolated from B cells of a MERS-CoV-infected human donor, and has been used to establish a stable CHO cell line from which clinical grade antibody is reliably available (Corti et al, 2016); this type of ready availability would be of particular benefit in KSA for outbreak situations. It had both prophylactic and therapeutic activities against MERS-CoV infection in 2 transgenic mouse models, Ad5/hDPP4 and type I interferon receptor (IFNAR)-KO (Corti et al, 2016). Another human anti-RBD antibody, 3B11-N, has shown promising results in a non-human primate model, i.e.…”

“…Targets both NTD and RBD; stable CHO cell line; prophylactic and therapeutic (Corti et al, 2016) Antibody (human): S1 RBD 3B11-N In vitro In vivo (rhesus monkeys)…”

Prophylactic efficacy of a human monoclonal antibody against MERS-CoV in the common marmoset

“…There are currently no approved treatments for MERS. LCA60 is a human IgG1 monoclonal antibody that was isolated from the memory B cells derived from a convalescent MERS patient in the UK (Bermingham et al, 2012;Corti et al, 2016) that neutralizes MERS-CoV by binding to the receptor binding domain of the MERS-CoV spike protein (Corti et al, 2015). Balb/c mice transiently expressing human DPP4 in lung tissue after transduction with an adenovirus vector expressing human DPP4 and treated with LCA60 one day before or after challenge with MERS-CoV showed a significant reduction of virus titers in the lungs compared to controls (Corti et al, 2015).…”