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

• Published in: Journal of allergy and clinical immunology Vol. 144; no. 2; pp. 514 - 523.e5
• Main Authors: Lua, Wai-Heng, Su, Chinh Tran-To, Yeo, Joshua Yi, Poh, Jun-Jie, Ling, Wei-Li, Phua, Ser-Xian, Gan, Samuel Ken-En
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-08-2019; Elsevier Limited
• Subjects: Allergies; Allergy; Allosteric properties; allostery; antibodies; Antibodies, Monoclonal, Humanized - chemistry; Antibodies, Monoclonal, Humanized - immunology; Antigens; Antigens, Bacterial - chemistry; Antigens, Bacterial - immunology; Biosensors; Chromatography; Complementarity; Computer applications; Computer simulation; ErbB-2 protein; Fc receptor binding; Humans; Hypersensitivity - immunology; Hypersensitivity - therapy; IgE; Immunoglobulin E; Immunoglobulin E - chemistry; Immunoglobulin E - immunology; Immunoglobulin E - therapeutic use; Immunoglobulin Heavy Chains - chemistry; Immunoglobulin Heavy Chains - immunology; Immunoglobulin Heavy Chains - therapeutic use; Immunoglobulin Variable Region - chemistry; Immunoglobulin Variable Region - immunology; Immunoglobulin Variable Region - therapeutic use; Immunoglobulins; Immunotherapy; Investigations; Microorganisms; Monoclonal antibodies; Omalizumab - chemistry; Omalizumab - immunology; Oncology; Protein A; Proteins; Receptors, IgE - chemistry; Receptors, IgE - immunology; Software; superantigen binding; Superantigens - chemistry; Superantigens - immunology; Targeted cancer therapy; Therapeutic applications; Trastuzumab; Trastuzumab - chemistry; Trastuzumab - immunology; variable heavy chain families; FWR; Allergy; spA; IgE; V-region; PDB; CDR; C-region; Fc receptor binding; VH; ka; variable heavy chain families; superantigen binding; KD; antibodies; allostery
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2019.03.028

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.
We sought to investigate the effects of VH families on IgE interaction with FcεRIα, anti-IgE omalizumab, antigen, and superantigen protein A (spA) by using the pertuzumab and trastuzumab IgE models.
Pertuzumab VH1–VH7 family variants of IgE with the same complementarity-determining regions were investigated with regard to their binding interactions to FcεRIα, Her2, omalizumab, and spA. Notable FcεRIα-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.
The pertuzumab VH5 IgE variant, but not the trastuzumab VH5 IgE, was found to interact with FcεRIα 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.
We found unexpected varying allosteric communications caused by the VH family FWRs to the FcεRIα-, 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.