Biochemical Prevention and Treatment of Respiratory Syncytial Virus Infection
The respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in infants and young children producing bronchiolitis and pneumonia worldwide. RSV infection leads to more than 90,000 hospitalizations and a 2% mortality rate among infants nationwide. Approximately two-thirds of infants are infected with RSV during the first year of life and approximately 95% of children test seropositive for RSV by the age of two. Unfortunately, even natural RSV infection produces limited immunity at best. In fact, an inactivated RSV vaccine paradoxically resulted in more severe disease instead of protection.
The most successful approach to date has been Biochemical Prevention and Treatment with anti-viral antibodies. In 1996, RespiGam™ (respiratory syncytial virus immune globulin or RSV-IG) became available for use in children less than two years of age with high-risk factors. The use of RespiGam™ was largely supplanted with the approval of Synagis™ (Palivizumab) in 1998. Palivizumab is an IgG1 MAb administered IM monthly that selectively binds to the RSV surface glycoprotein F. The drug specifically inhibits RSV replication by preventing the virus from fusing with the respiratory endothelial cell membrane. Palivizumab has been shown to reduce the rate of hospitalization of at-risk infants by about 55% in clinical studies and now serves as the primary medical means of RSV prevention.
Prevention of Human Rhinovirus infections
Human rhinovirus (HRV) causes over 80% of the common cold in the fall. Developing vaccines against HRV is unfeasible because HRVs have at least 115 antigenically distinct serotypes. One of the proven methods to prevent and inhibit viral infections is to block host cell receptors that are used by viruses to gain cell entry. Receptor blockage is commonly achieved via application of MAbs that bind to specific epitopes on the receptor molecules. A plethora of in vitro studies have reported effective viral inhibition by receptor-blocking MAbs. However, these works have not yielded yet any approved drug on the market.
In HRV infection, about 90% of HRV serotypes utilize a single cell surface receptor exclusively, which is the intercellular adhesion molecule-1 (ICAM-1), for viral attachment and subsequent viral entry. As such, ICAM-1 has become a very promising target for biochemical prevention. A receptor blocking approach has shown that the soluble ICAM-1 and an anti-ICAM-1 monoclonal antibody, Mab 1A6, could prevent infections by a broad spectrum of rhinovirus serotypes in human cells in vitro. Administration of soluble ICAM-1 and MAbs in human clinical trials had indeed achieved reduction in symptoms, but did not prevent the incidence of the disease. For the MAbs, the limited efficacy is most likely due to its low functional affinity (or avidity) for ICAM-1 when compared to that of the multivalent HRV particles.
High avidity is achieved by multivalency. To improve avidity of HRV receptor blocking antibody, a novel tetravalent recombinant antibody, CFY196, has been generated against ICAM-1 [26]. CFY196 is composed of Fab fragment of a humanized version of MAb 1A6 fused with a linker derived from human immunoglobulin D (IgD) hinge and a tetramerization domain derived from the coiled-coil sequence of human transcription factor ATFα. CFY196 is expressed in bacteria and purified as a homogenous tetrameric molecular complex. CFY196 exhibited almost two-orders-of-magnitude improvement in functional affinity compared with its bivalent counterpart based on the kinetic parameters measured by BIAcore analysis. Such kinetic improvement also directly leads to functional superiorities of CFY196. In in vitro assays, CFY196 consistently and significantly outpaced the best commercial anti-ICAM-1 MAbs in preventing HRV infection as measured by reduction of cytopathic effects and HRV viral titers. The preclinical findings of CFY196 bode well its efficacy in human since MAb 1A6, from which CFY196 is derived, has already exhibited positive effects in a human trial. Moreover, to prevent possible immunogenicity, CFY196 is humanized. Further pre-clinical and clinical development of CFY196 is warranted to fully evaluate its potential as a prophylaxis and therapeutics for the HRV induced common colds.