Abstract
Staphylococcal enterotoxin B (SEB) simultaneously crosslinks MHC class II antigen and TCR, promoting proliferation of T cells and releasing a large number of toxic cytokines. In this report, we computationally examined the possibility of using a single-chain biparatopic bispecific antibody to target SEB and prevent TCR binding. The design was inspired by the observation that mixing two anti-SEB antibodies 14G8 and 6D3 can block SEB-TCR activation, and we used 14G8-6D3-SEB tertiary crystal structure as a template. Twelve simulation systems were constructed to systematically examine the effects of the designed bispecific scFV MB102a, including isolated SEB, MB102a with different linkers, MB102a-SEB complex, MB102a-SEB-TCRβ complex, MB102a-SEB-TCR-MHC II complex, and MB102a-SEB-MHC II. Our all atom molecular dynamics simulations (total 18,900 ns) confirmed that the designed single-chain bispecific antibody may allosterically prevent SEB-TCRβ chain binding and inhibit SEB-TCR-MHC II formation. Subsequent analysis indicated that the binding of scFV to SEB correlates with SEB-TCR binding site motion and weakens SEB-TCR interactions.
Highlights
Bispecific antibodies contain two different antigen-binding sites in one molecule
Extensive molecular dynamics simulations have shown that the binding of the designed bispecific scFv with Staphylococcal enterotoxin B (SEB) allosterically prevents SEB-TCR association and formation of SEB-MHC-TCR complexes
Subsequent analysis indicated that the binding of scFV to SEB correlates with SEB-TCR binding site motion and weakens SEBTCR interactions
Summary
Bispecific antibodies contain two different antigen-binding sites in one molecule. Biparatopic bispecific antibodies recognize two different epitopes on one molecule and are promising formats for the development of next-generation antibody therapeutics [10,11,12,13]. It is interesting to examine a novel approach to use a biparatopic antibody to target Staphylococcal enterotoxin B (SEB), a small single domain protein with at least four non-overlapping epitopes. 20B1 binds on the TCR binding site, preventing the formation of MHC-TCR-SEB complex, it has the more prominent neutralization [21, 23]. Extensive molecular dynamics simulations have shown that the binding of the designed bispecific scFv with SEB allosterically prevents SEB-TCR association and formation of SEB-MHC-TCR complexes. Subsequent analysis indicated that the binding of scFV to SEB correlates with SEB-TCR binding site motion and weakens SEBTCR interactions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
