Molecular Insights of Nickel Binding to Therapeutic Antibodies as a Possible New Antibody Superantigen

Abstract

The binding of nickel by immune proteins can manifest as Type IV contact dermatitis (Ni-specific T cells mediated) and less frequently as Type I hypersensitivity with both mechanisms remaining unknown to date. Since there are reports of patients co-manifesting the two hypersensitivities, a common mechanism may underlie both the TCR and IgE nickel binding. Focusing on Trastuzumab and Pertuzumab IgE variants as serendipitous investigation models, we found Ni-NTA interactions independent of Her2 binding to be due to glutamine stretches. These stretches are both Ni-inducible and in fixed pockets at the antibody complementarity-determining regions (CDRs) and framework regions (FWRs) of both the antibody heavy and light chains with influence from the heavy chain constant region. Comparisons with TCRs structures revealed similar interactions, demonstrating the possible underlying mechanism in selecting for Ni-binding IgEs and TCRs respectively. With the elucidation of the interaction, future therapeutic antibodies could also be sagaciously engineered to utilize such nickel binding for biotechnological purposes.

Superantigen Recognition and Interactions: Functions, Mechanisms and Applications

“…The observation that B-cell superantigens, and more specifically superantigen-Fab complexes, are physicochemically similar may allow for development of engineering strategies which makes use of this facility. Nonetheless, just as we expanded the definition of superantigens in this review to include B-cell activation based on new findings, we are also aware of novel superantigen-like behaviours by non-proteins e.g., nickel (133) that may in time be included as superantigens in the future.…”

Sagacious Epitope Selection for Vaccines, and Both Antibody-Based Therapeutics and Diagnostics: Tips From Virology and Oncology<strong> </strong>

“…Antigens have the potential to bind antibodies in non-conventional CDR-dependent manner by inducing binding pockets or the formation of stretches/patches on antibodies. This phenomenon was observed for non-conventional immunogenic molecule such as nickel 45 binding to Trastuzumab and Pertuzumab that can possibly underlie the disease pathogenesis of nickel type-I allergy. The other example of induced binding is in the molecular dynamics (MD) simulation of Trastuzumab binding to Her2, inducing a cryptotopes that facilitated Pertuzumab binding 46 .…”

Peering into Avian Influenza A(H5N8) for a Framework towards Pandemic Preparedness

“…This combinatorial approach of computational and experimental research has been previously applied in the COVID-19 pandemic, for both drug repurposing [128] and synergistic drug combinations [129]. Such knowledge, when coupled with antibody engineering [130], could also lead to development of better neutralizing antibodies, particularly if they are of mucosal antibodies of IgA [131] or even IgE [132,133], capable of recognizing superantigen elements [134] as the SARS-CoV-2 spike [135].…”