Potent neutralization of botulinum neurotoxin by recombinant oligoclonal antibody.
The botulinum neurotoxins (BoNTs) cause the paralytic human disease botulism and are one of the highest-risk threat agents for bioterrorism. To generate a pharmaceutical to prevent or treat botulism, monoclonal antibodies (mAbs) were generated by phage display and evaluated for neutralization of BoNT serotype A (BoNT/A) in vivo. Although no single mAb significantly neutralized toxin, a combination of three mAbs (oligoclonal Ab) neutralized 450,000 50% lethal doses of BoNT/A, a potency 90 times greater than human hyperimmune globulin. The potency of oligoclonal Ab was primarily due to a large increase in functional Ab binding affinity. The results indicate that the potency of the polyclonal humoral immune response can be deconvoluted to a few mAbs binding nonoverlapping epitopes, providing a route to drugs for preventing and treating botulism and diseases caused by other pathogens and biologic threat agents.
Nowakowski
A
A
Department of Anesthesia and Pharmaceutical Chemistry, University of California, Room 3C-38, San Francisco General Hospital, 1001 Potrero Avenue, San Francisco, CA 94110, USA.
Wang
C
C
Powers
D B
DB
Amersdorfer
P
P
Smith
T J
TJ
Montgomery
V A
VA
Sheridan
R
R
Blake
R
R
Smith
L A
LA
Marks
J D
JD
D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000918:Antibody Specificity; D001483:Base Sequence; D001905:Botulinum Toxins / Q000276:immunology*; D017931:DNA Primers; D007074:Immunoglobulin G / Q000276:immunology*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D007700:Kinetics; D008297:Male; D051379:Mice; D009500:Neutralization Tests; D010791:Phrenic Nerve / Q000276:immunology; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000276:immunology; D013997:Time Factors
D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D017931:DNA Primers; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D011994:Recombinant Proteins; D001905:Botulinum Toxins