Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo

Abstract

As of 13 November 2015, 1618 laboratory-confirmed human cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection, including 579 deaths, had been reported to the World Health Organization. No specific preventive or therapeutic agent of proven value against MERS-CoV is currently available. Public Health England and the International Severe Acute Respiratory and Emerging Infection Consortium identified passive immunotherapy with neutralizing antibodies as a treatment approach that warrants priority study. Two experimental MERS-CoV vaccines were used to vaccinate two groups of transchromosomic (Tc) bovines that were genetically modified to produce large quantities of fully human polyclonal immunoglobulin G (IgG) antibodies. Vaccination with a clade A g-irradiated whole killed virion vaccine (Jordan strain) or a clade B spike protein nanoparticle vaccine (Al-Hasa strain) resulted in Tc bovine sera with high enzyme-linked immunosorbent assay (ELISA) and neutralizing antibody titers in vitro. Two purified Tc bovine human IgG immunoglobulins (Tc hIgG), SAB-300 (produced after Jordan strain vaccination) and SAB-301 (produced after Al-Hasa strain vaccination), also had high ELISA and neutralizing antibody titers without antibody-dependent enhancement in vitro. SAB-301 was selected for in vivo and preclinical studies. Administration of single doses of SAB-301 12 hours before or 24 and 48 hours after MERS-CoV infection (Erasmus Medical Center 2012 strain) of Ad5-hDPP4 receptor-transduced mice rapidly resulted in viral lung titers near or below the limit of detection. Tc bovines, combined with the ability to quickly produce Tc hIgG and develop in vitro assays and animal model(s), potentially offer a platform to rapidly produce a therapeutic to prevent and/or treat MERSCoV infection and/or other emerging infectious diseases.

Passive immunotherapy for Middle East Respiratory Syndrome coronavirus infection with equine immunoglobulin or immunoglobulin fragments in a mouse model

“…However, the single clone antibody raises the concern of viral escape mutant when applied to human. Administration of transchromosomic bovine human immunoglobulins (Luke et al, 2016) or dromedary immune serum resulted in rapidly viral clearance in infected mouse lungs. The disadvantage of these antibodies is that these animals are not readily available.…”

Non-antibiotic treatments for bacterial diseases in an era of progressive antibiotic resistance

“…Active immunizations with adjuvanted, multi-eptitope bacterial vaccines are in development, as are monoclonal and polyclonal antibodies, as passive therapies against bacterial pathogens [9–11]. Transchromosomic cattle have been developed that can deliver high volumes of high quality, human polyclonal antibodies against bacterial and viral antigens [11].…”

“…Active immunizations with adjuvanted, multi-eptitope bacterial vaccines are in development, as are monoclonal and polyclonal antibodies, as passive therapies against bacterial pathogens [9–11]. Transchromosomic cattle have been developed that can deliver high volumes of high quality, human polyclonal antibodies against bacterial and viral antigens [11]. Monoclonal antibodies can be designed with advantageous features and half-lives that can opsonize bacteria or inhibit virulence factors without the need for antibiotics [9, 10].…”

Development of Medical Countermeasures to Middle East Respiratory Syndrome Coronavirus

“…Platforms are being developed to rapidly discover monoclonal antibodies, either from fully human convalescent blood or from transgenic animals, which can be manufactured on a large scale and are likely to have a good safety profile. The most advanced immunotherapeutic for MERS-CoV uses a transchromosomal bovine production system to produce fully human polyclonal MERS-CoV antibodies; a phase I study of this produce was recently implemented ( 57 ; https://clinicaltrials.gov/ct2/show/NCT02788188). Preliminary results from immunoprophylaxis or treatment studies have shown efficacy of fully human monoclonal or polyclonal antibodies in MERS-CoV-infected mice and NHPs (Table 4).…”