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.
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.
|Sharma, Rashmi; Zhao, Huiwu; Al-Saleem, Fetweh H et al. (2014) Mechanisms of enhanced neutralization of botulinum neurotoxin by monoclonal antibodies conjugated to antibodies specific for the erythrocyte complement receptor. Mol Immunol 57:247-54|
|Benefield, Desiree A; Dessain, Scott K; Shine, Nancy et al. (2013) Molecular assembly of botulinum neurotoxin progenitor complexes. Proc Natl Acad Sci U S A 110:5630-5|
|Adekar, Sharad P; Segan, Andrew T; Chen, Cindy et al. (2011) Enhanced neutralization potency of botulinum neurotoxin antibodies using a red blood cell-targeting fusion protein. PLoS One 6:e17491|
|Adekar, Sharad P; Al-Saleem, Fetweh H; Elias, M D et al. (2008) A natural human IgM antibody that neutralizes botulinum neurotoxin in vivo. Hybridoma (Larchmt) 27:65-9|
|Dessain, S K; Adekar, S P; Berry, J D (2008) Exploring the native human antibody repertoire to create antiviral therapeutics. Curr Top Microbiol Immunol 317:155-83|
|Adekar, Sharad P; Jones, R Mark; Elias, M D et al. (2008) A human monoclonal antibody that binds serotype A botulinum neurotoxin. Hybridoma (Larchmt) 27:11-7|
|Adekar, Sharad P; Jones, R Mark; Elias, M D et al. (2008) Hybridoma populations enriched for affinity-matured human IgGs yield high-affinity antibodies specific for botulinum neurotoxins. J Immunol Methods 333:156-66|
|Adekar, Sharad P; Takahashi, Tsuyoshi; Jones, R Mark et al. (2008) Neutralization of botulinum neurotoxin by a human monoclonal antibody specific for the catalytic light chain. PLoS One 3:e3023|