Do Therapeutic Antibodies Hold the Key to an Effective Treatment for Ebola Hemorrhagic Fever?

Abstract

linked by a disulfide bond. The GP1 subunit mediates viral attachment, most likely through the mucin-like region or the putative receptorbinding region. The GP2 subunit has the heptad repeat regions required for assembling the GP as a trimer. The hydrophobic fusion loop on GP2 is thought to catalyze fusion of the viral envelope and host cell membrane. Previous studies focusing on the interaction between GPs and neutralizing monoclonal antibodies (mAbs) indicate that direct inhibition of GP attachment to the cell surface or endosomal receptors, and blocking fusion of viral and host membranes, are likely to be key mechanisms of neutralization [1]. Preventing proteolytic processing, such as cleavage by cathepsin, is another possibility, but remains controversial [2,3]. The presence of neutralizing antibodies to filoviruses has been confirmed in the sera of convalescent patients and experimentally infected nonhuman primates. Passive immunization with antibodies against filoviruses began to be tested in the early years, but its protective efficacy remained elusive [4]. In some clinical cases, convalescent human sera were used in treatment, together with several drugs [4]. However, reliable conclusions could not be drawn from these studies due to possible effects of concomitant drugs and to the inevitable lack of adequate control studies. The protective efficacy of passive immunization with hyperimmune sera and purified polyclonal and monoclonal antibodies was shown to be effective in rodent models, whereas evidence of protective efficacy in primates was lacking. In particular, a recombinant human mAb, which was generated using phage display libraries constructed from RNA derived from convalescent patients, was shown to be protective in rodent models [5]; however, this mAb failed to protect rhesus macaques from lethal Ebola virus challenge [6]. Filoviruses, including Ebola and Marburg viruses, are enveloped, negative-stranded RNA viruses. These viruses cause severe hemorrhagic fever in humans and nonhuman primates, and are classified as biosafety level 4 agents. Past outbreaks of Ebola and Marburg hemorrhagic fever in humans (other than imported) were sporadic in central and west Africa. Increasingly frequent outbreaks in sub-Saharan Africa and bioterrorism concerns over the last few decades have emphasized the danger to public health, but no effective prophylaxis or treatment is, as yet, commercially available. While the efficacy of passive immunization with convalescent human sera used for treatment in clinical cases is controversial, recent studies have demonstrated that antibody treatments can protect nonhuman primates and open avenues for the therapeutic use of antibodies against filovirus infections.