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Generation and characterization of high affinity human monoclonal antibodies that neutralize staphylococcal enterotoxin B
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Generation and characterization of high affinity human monoclonal antibodies that neutralize staphylococcal enterotoxin B
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Generation and characterization of high affinity human monoclonal antibodies that neutralize staphylococcal enterotoxin B
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Journal Article
Generation and characterization of high affinity human monoclonal antibodies that neutralize staphylococcal enterotoxin B
2010
Overview
Background
Staphylococcal enterotoxins are considered potential biowarfare agents that can be spread through ingestion or inhalation. Staphylococcal enterotoxin B (SEB) is a widely studied superantigen that can directly stimulate T-cells to release a massive amount of proinflammatory cytokines by bridging the MHC II molecules on an antigen presenting cell (APC) and the Vβ chains of the T-cell receptor (TCR). This potentially can lead to toxic, debilitating and lethal effects. Currently, there are no preventative measures for SEB exposure, only supportive therapies.
Methods
To develop a potential therapeutic candidate to combat SEB exposure, we have generated three human B-cell hybridomas that produce human monoclonal antibodies (HuMAbs) to SEB. These HuMAbs were screened for specificity, affinity and the ability to block SEB activity
in vitro
as well as its lethal effect
in vivo
.
Results
The high-affinity HuMAbs, as determined by BiaCore analysis, were specific to SEB with minimal crossreactivity to related toxins by ELISA. In an immunoblotting experiment, our HuMAbs bound SEB mixed in a cell lysate and did not bind any of the lysate proteins. In an
in vitro
cell-based assay, these HuMAbs could inhibit SEB-induced secretion of the proinflammatory cytokines (INF-γ and TNF-α) by primary human lymphocytes with high potency. In an
in vivo
LPS-potentiated mouse model, our lead antibody, HuMAb-154, was capable of neutralizing up to 100 μg of SEB challenge equivalent to 500 times over the reported LD
50
(0.2 μg) , protecting mice from death. Extended survival was also observed when HuMAb-154 was administered after SEB challenge.
Conclusion
We have generated high-affinity SEB-specific antibodies capable of neutralizing SEB
in
vitro as well as
in vivo
in a mouse model. Taken together, these results suggest that our antibodies hold the potential as passive immunotherapies for both prophylactic and therapeutic countermeasures of SEB exposure.
Publisher
BioMed Central
Subject
