Role of the IgE variable heavy chain in FcεRIα and superantigen binding in allergy and immunotherapy

Background: Variable heavy chain (VH) family frameworks (FWRs) have been reported to affect antibody receptor and superantigen binding; however, such effects in IgE remain largely unknown. Given that VH family biases have been previously reported in IgE of certain allergies, there is a need to investigate this phenomenon for biotechnological and therapeutic purposes. Objective: We sought to investigate the effects of VH families on IgE interaction with Fc epsilon RI alpha, anti-IgE omalizumab, antigen, and superantigen protein A (spA) by using the pertuzumab and trastuzumab IgE models. Methods: Pertuzumab VH1-VH7 family variants of IgE with the same complementarity-determining regions were investigated with regard to their binding interactions to Fc epsilon RI alpha, Her2, omalizumab, and spA. Notable Fc epsilon RI alpha-IgE observations were cross-checked against appropriate trastuzumab IgE VH variants. Computational structural modeling and simulations were also performed for insight into the mechanism of interactions with various VH FWRs. Results: The pertuzumab VH5 IgE variant, but not the trastuzumab VH5 IgE, was found to interact with Fc epsilon RI alpha significantly longer than the respective VH family variants within each model antibody. No significant differences in interaction were found between IgE and omalizumab for the pertuzumab VH variants. Although trastuzumab VH3 interacted with spA, none of our pertuzumab VH variants, including VH3, associated with spA. Conclusion: We found unexpected varying allosteric communications caused by the VH family FWRs to the Fc epsilon RI alpha-, Her2-, and spA-binding regions of pertuzumab IgE, with implications for use of IgE/anti-IgE therapeutics to treat allergy and IgE therapeutics in allergo-oncology.