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

Abstract

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 FcεRIa, 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 FcεRIa, Her2, omalizumab, and spA. Notable FcεRIa-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 FcεRIa 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 FcεRIa-, 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.

Not all therapeutic antibody isotypes are equal: the case of IgM versus IgG in Pertuzumab and Trastuzumab

“…21,24,34,35 Previous experimental and computational studies of IgG and IgA have suggested that the Fc and Fab regions of an antibody might communicate with one another; 23,25 for example, point mutations in the Fc region may reduce binding affinity, whilst antigen binding to the Fab region changes the conformation of the Fc domain to promote binding to its receptor. 22,24,36,37 Allostery between the different subunits in a multimeric IgM, however, remains elusive. Our multiscale simulation study indicates that the individual Fab domains are free to move independently of one another and do not affect the motion of their neighbors.…”

“…A molecular-level understanding of how such distinct binding avidities arise for the same antigen is of importance for future design of therapeutic antibodies and epitope selection. Given that we have previously showed that antibody-antigen interactions can be drastically affected by small changes in the antibody light chain, 21 antibody hinge, 22 V-region pairing, 23 and VH families, 24 it may be necessary to study the whole IgM molecule using a holistic approach. 25 Thus, we now report the rst integrative models of fulllength Pertuzumab and Trastuzumab IgM multimers, based initially on available X-ray and NMR structures for each Ig domain.…”

An alternative HIV-1 non-nucleoside Reverse Transcriptase inhibition mechanism: Targeting the p51 subunit

“…Since viruses can develop cross-resistance to multiple drugs [21,43], and Y183 has yet to have a reported clinical mutation, compound 2 serves as a potentially important guide for targeting drug-resistant HIV-1 variants, and with the conservation of the site across RTs -a possible broad-spectrum RTI as well. By taking a holistic approach [44] in studying the whole structure of the target proteins and looking for common sites and how resistance develops, as demonstrated for HIV-1 Gag [45], HIV-1 Protease [43], and antibodies [46][47][48][49][50][51], the search for common druggable conserved sites across protein families can add to the success of developing broad-spectrum therapeutics.…”

Molecular insight into Nickel(II) binding by Her2-specific IgE: a possible mechanistic insight into the pathogenesis of Type I nickel hypersensitivity

“…While less frequent than in type IV, nickel could elicit type I hypersensitivity through "nonantigenic" mechanism via IgE (Malo et al, 1985) and was postulated to act as a mast cell discharger (Walsh et al, 2010). It is possible that Ni 2+ binding may involve mechanisms apart from CDRs alone, requiring a whole antibody holistic investigation (Phua et al, 2019) given that the various regions of the antibody interact together to affect antigen binding (Lua et al, 2018;Su et al, 2018) and even receptor engagement (Ling et al, 2018;Lua et al, 2019), with the possibility of these regions coming synergistically to form histidine rich areas to bind Ni 2+ .…”