Multivalent therapeutic proteins for influenza

Influenza continues to be a global threat with the potential for great loss of life and disruption to society and commerce. Governments have been stockpiling huge amounts of the two antivirals Relenza and Tamiflu, both of which are $1 billion drugs. The influenza virus has the capacity to mutate or to generate completely new viruses, in terms of their assault on our immune system, through mixing of its genetic segments. Sadly, circulating H1N1 viruses have already developed resistance to Tamiflu. Vaccines are generally effective, but take a long time to generate and recent vaccines for pandemic swine H1N1 have had reported side effects. We are taking the novel approach of blocking the attachment sites in the respiratory tract that the influenza virus requires for infection. We have developed proteins that bind tightly to these receptors (sugar molecules called sialic acids), and they halt a lethal infection of influenza in a mouse model. Our approach has the potential to be a drug against any current and future strain of influenza and potentially parainfluenza that uses the same receptors, and could be a first line of defence in a pandemic or a prophylactic for high-risk patients.

Influenza continues to be a global health threat, with a constant requirement for new therapies. We have approached this need by engineering a panel of multivalent proteins constructed using carbohydrate-binding modules derived from the Vibrio cholerae and Streptococcus pneumoniae sialidases. These multivalent proteins have up to nanomolar binding affinity for sialic acid - the binding receptor for (para)influenza viruses - found on mammalian cell surfaces of the respiratory tract. Preliminary in vivo studies in mice have shown that they are tolerant to the proteins, and that they are effective in preventing disease when applied one day before or on the day of viral infection. We propose that these multivalent proteins be considered as biologics for use as a prophylactic against pandemic influenza. We will carry out further in vivo studies (at Edinburgh and at St Jude, Memphis) to examine dosage and delivery of the proteins and will study any immune response elicited by them, and devise de-immunisation strategies if neccessary. The aim is to identity a lead biologic for further development. We believe that this approach of targeting the host rather than the virus should minimize problems of drug resistance.