Perspective: The promises of a holistic view of proteins—impact on antibody engineering and drug discovery

Phua, Ser-Xian; Chan, Kwok-Fong; Su, Chinh Tran-To; Poh, Jun-Jie; Gan, Samuel Ken‐En

doi:10.1042/bsr20181958

Cited by 32 publications

(44 citation statements)

References 83 publications

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“…Thus future allergen-specific IgE studies and engineering of therapeutic IgEs would benefit from analyzing specific IgEs as a whole rather than as a sum of regions or domains. 55 Although we were able to artificially create a more persistent IgE with V-regions that augmented FcεRIa engagement in the rare pertuzumab VH5 IgE (the only of 10 recombinant IgEs we produced), the discovery for such a patient-derived IgE would certainly change the understanding of the role of IgE V-regions in allergy pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

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

Lua

Yeo

et al. 2019

Journal of Allergy and Clinical Immunology

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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.

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Section: Discussionmentioning

confidence: 99%

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

Lua

Yeo

et al. 2019

Journal of Allergy and Clinical Immunology

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Chan

Krah

et al. 2019

Preprint

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Since drug resistance mutations in HIV-1 have been increasingly reported to resist most of the current drug repertoire in the antiretroviral therapy, there is a demand for new drugs. In this study, we focused on the viral enzyme Reverse Transcriptase (RT) as it is a good drug target given its absence in non-viruses. Through a reverse transcription assay screen, we found two out of forty compounds from the NCI Diversity Set V to inhibit HIV-1 RT activity. The less potent compound also inhibited MMLV RT. Molecular docking, structural conservation and binding pocket analyses suggested similar binding mechanisms of the dual inhibitor to the targets, implying that the phenylbenzoic scaffold may be potentially used to design broad-spectrum inhibitors against multiple Reverse Transcriptase enzymes from multiple viruses.

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“…Allosteric modulation has been an area of interest in molecular immunology (Janda et al, 2016;Lua et al, 2019;Su et al, 2017;Yang et al, 2017). 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 Phua et al, 2019); for example, point mutations on 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 (Lua et al, 2019;Oda et al, 2003;Schlessinger et al, 1975;Su et al, 2018). Allostery between the different subunits in a multimeric IgM, however, remain elusive.…”

Section: Discussionmentioning

confidence: 99%

The structural basis for distinct binding avidity of Pertuzumab and Trastuzumab IgM towards HER2

Samsudin

Yeo

Gan

et al. 2019

Preprint

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Harnessing the therapeutic potential of immunoglobulin M (IgM) is of considerable interest in immunotherapy due to its complement-activating and cell-agglutinating abilities. Pertuzumab and Trastuzumab are monoclonal antibody drugs used in therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer but exhibit significantly different binding affinities as IgM when compared to the original IgG1 form. While the affinity of Pertuzumab IgM to the HER2 extracellular domain is about one order of magnitude higher than IgG1 in experiments, it was recently reported that Trastuzumab IgM and IgG have similar equilibrium dissociation constants to one another. We now perform an integrative multiscale simulation study in order to understand the structural basis for the differences in behavior between the two antibodies, based on complete antibody assemblies. We show that Pertuzumab IgM is able to utilize all of its V-regions to engage HER2 in a more stable mode than Trastuzumab IgM due to steric clashes between the large globular HER2 domains when bound to Trastuzumab. This is subsequently validated by confirming that Pertuzumab IgM inhibits proliferation in HER2 overexpressing live cells more effectively than its IgG1 counterpart. Given the widespread clinical use of Trastuzumab and Pertuzumab, elucidating the molecular details of antibody-antigen interaction may help guide the choice of epitopes for future design and selection of improved therapeutic antibody isotypes.

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Perspective: The promises of a holistic view of proteins—impact on antibody engineering and drug discovery

Cited by 32 publications

References 83 publications

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

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

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

The structural basis for distinct binding avidity of Pertuzumab and Trastuzumab IgM towards HER2

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