Therapeutics to Any Pathogen in 7 Days

Project: Research project

Description

Our Center has been working on technologies relative to biothreats for the warfighter since 1996. We have come to the conclusion that there are two broad technical areas that need to be advanced if we are to be as prepared as possible for known and unknown threats. The first is a technology for host-based, pre-symptomatic detection of infections. Relative to this need, we have developed a technology we term immunosignaturing that is a simple, inexpensive method to monitor a persons health status on a continual basis. The second technical requirements are platform technologies that would allow rapid response for protecting the warfighter against any pathogen once it is detected. This has proved a larger challenge. What are the logical opportunities in this regard? One is to have a general agent that will work against any pathogen. On the pathogen side this could be a single or a few broad acting anti-bacterial or anti-viral agents. DARPA has funded such projects in the past. Such agents would probably not be used in standard care, as they would be likely to have more side effects. Critically, to depend on these agents would leave us vulnerable to genetic work-arounds of the pathogens susceptibility. On the host side, the idea is to use agents that broadly stimulate a protective innate response that would take care of any pathogen. DARPA did fund projects to use CpGs, cytokine mixtures or parapox (our funded project) to attempt this. While this concept is quite attractive, it has not worked broadly enough to be useful, at least to date. Our feeling is that the silver bullet strategy will be very difficult to accomplish because it must work against the stabilizing systems that organisms have evolved. This approach will also inherently have more side effects and therefore be difficult to commercialize. The second general logic is to make a reagent specific to the pathogen. One form of this strategy is that we create treatments for all the possible pathogens that might be used. This is not a good option. There are over 200 known potential viral and ~40 bacterial pathogens with more being discovered each year. It would not be technically, logistically or economically feasible to prepare large stocks of diverse, single treatments. The BAA announcement suggested several other approaches that are worth considering, such as passive transfer from infected individuals and general methods to make the host more resistant or the pathogen more sensitive. However, there is another logical approach that we have taken. That is, that a system be developed that could make a specific therapeutic agent to any new pathogen very, very fast. We have created such a system. I was posed was posed the question of how to make a therapeutic in a week by DARPA and the Biochem 20/20 group ~7 years ago. I first considered a drastic improvement on existing technologies for developing therapeutics by screening libraries. It is conceivable that one could pan a library of small molecules, antibodies or antibody like molecules (e.g. aptamers) in two weeks or less. The problem is that even if this were possible one could not make a large stock of the selected agent in a short time. The solution is to break with the small molecule/antibody binding paradigm. If one makes the binding of the target bacterium or virus a combinatorial event, then one could have large stocks of agents ready to be combined to produce large amounts of protective therapeutics. This is one element of our innovation: There are two other critical innovations in the process we developed that are critical to make this innovation work. The idea of linking two weak binding elements to create a high affinity one was first proposed and demonstrated by Fesik and colleagues (1). They linked two weak binding small molecules to create a high affinity drug. However, the process was long and laborious, requiring solving the structure of the target. For this re
StatusFinished
Effective start/end date7/15/107/14/12

Funding

  • DOD: Defense Advanced Research Projects Agency (DARPA): $5,353,003.00

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therapeutics
pathogens
antibodies
adverse effects
antiviral agents
health status
cytokines
screening
drugs
viruses
monitoring
bacteria
organisms
methodology
infection