We propose a platform which will radically change the current approach to antitoxin development by introducing a new strategy that will permit rapid development and commercialization of safe, effective antitoxin products having low development and product costs and long shelf lives. Toxins from microbial and other sources continue to cause substantial human and veterinary pathology and are serious Category A and B biosecurity threats. Treatment for toxin exposure is generally limited to the availability of antitoxin agents. Antibody and antisera products are difficult and expensive agents to prepare in large quantities and have problematic quality control and safety issues and limited shelf life. This is a particularly serious problem for stockpiling and storing antitoxins in preparation of possible bioterrorist events. We have found that a pool of small toxin binding agents, each with a common epitopic tag, will potently protect mice against intoxication when administered with a single anti-tag mAb. In this proposal, we will develop tagged, camelid VHH-based botulinum neurotoxin (BoNT) and Shiga toxin binding agents as anti-toxins. We will optimize the delivery format and test the antitoxin efficacy of the agents co-administered with monoclonal anti-tag antibodies of different isotypes. Through this proposal, antitoxin agents capable of protecting against intoxication with two different BoNT serotypes (A and B) and two different Shiga toxins (Stx1 and 2) will be developed and taken through in vivo testing. If successful, this strategy should have widespread application in antitoxin development, and possibly other therapies in which accelerated clearance of a target is required. The VHHbased products will be economical to produce at scale with long shelf-life and low toxicity

Public Health Relevance

This project will develop a promising, broad new antitoxin strategy, employing as prototypes shiga and botulinum toxins. Both toxins are serious biosecurity threats and each cause foodborne diseases against which currently there is no effective therapy. For example, Shiga toxin from E. coli O157 is a frequent cause of kidney failure in children (e.g. spinach outbreak in 2006).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057159-09
Application #
8375446
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2012
Total Cost
$486,911
Indirect Cost
$140,933
Name
Harvard University
Department
Type
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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