Lab research for the development of anti-diphetheria antibodies in humans

Diphtheria is an acute bacterial disease with a considerable case fatality rate caused by toxigenic Corynebacteria. Diphtheria toxin (DT) is the major virulence factor for these organisms. DT is synthesized and secreted as a single-polypeptide pro-enzyme that is cleaved and reduced in vivo to produce a toxic protein consisting of A and B fragments (1). DT has an estimated lethal dose for humans of ≤ 0.1 µg/kg (2). Because of widespread childhood vaccination, diphtheria is increasingly rare in developed countries, but when cases do arise they can be severe and require a rapid and robust public health response. Case fatality rates worldwide remain high (>10%) (3). The most effective treatment for diphtheria is early diphtheria antitoxin (DAT) administration, along with appropriate antibiotic therapy to eliminate Corynebacteria from the infection site, thus stopping toxin production. DAT is a preparation of immunoglobulins or immunoglobulin F(ab’)2 fractions, produced from immunized horses, that neutralizes circulating DT. Unfortunately, the supply of equine DAT has become increasingly problematic to secure. It is no longer manufactured in the US and is currently imported from Brazil (4). In addition, hypersensitivity reactions occur in about 20% of people treated with equine DAT. Neutralizing human (or humanized) monoclonal antibodies (mAbs) against DT are likely to be a safer, more reliable therapeutic for diphtheria.