Botulinum neurotoxin (BoNT) is the most potent biological toxin known, the cause of the paralytic disease, botulism, and a potential bioterrorist weapon. Passive immunization with antibody therapeutics is considered to be the ideal countermeasure for a BoNT exposure, and the safest of these would be composed of human monoclonal antibodies. An important obstacle to the production of an effective antibody therapeutic strategy for BoNT is that BoNT exists in at least 7 serotypes, and most of the antibodies cloned thus far are not able to bind more than one serotype. In addition, effective neutralization requires that triplet combinations of antibodies be employed, so that neutralization of 3 toxin serotypes would require at least 9 distinct antibodies. This project addresses this problem by exploring a platform for the creation of human monoclonal antibody therapeutics capable of binding and neutralizing three distinct serotypes of BoNT, A, B, and E. The foundation of the plan is a hybridoma method of human antibody cloning that has generated a number of cross-reactive antibodies. This is combined with a novel means of increasing the in vivo potency of BoNT antibodies using a fusion peptide that may increase the rate of clearance of BoNT from the bloodstream. An important aspect of the study is an ultra-high sensitivity ELISA, developed using human monoclonal antibodies, which will allow pharmacokinetic study of low doses of BoNT bound to antibody:fusion peptide complexes in real-world in vivo exposure scenarios.

Public Health Relevance

Botulinum neurotoxin (BoNT) has been listed as a Category A Select Bioterror agent by the Centers for Disease Control. Generation and study of multi-serotype-specific human antibodies, in combination with a novel technology for increasing BoNT clearance from the bloodstream, will help in the creation of a comprehensive therapeutic strategy for botulism or a BoNT bioterror attack. It will also provide a broad understanding of how similar approaches could be used to treat a variety of infectious diseases and toxin exposures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI065967-09
Application #
8432427
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Ranallo, Ryan
Project Start
2005-07-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
9
Fiscal Year
2013
Total Cost
$442,579
Indirect Cost
$128,669
Name
Lankenau Institute for Medical Research
Department
Type
DUNS #
125797084
City
Wynnewood
State
PA
Country
United States
Zip Code
19096
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