The synergistic effects of the constant region and variable heavy chain families of multimeric immunoglobulin M on its interaction with Fc-mu receptor and antigen

Document Type

Article

Publication Date

1-1-2022

Abstract

Aim: As the primary response antibody with increasing use as a therapeutic immunoglobulin (Ig) format, IgM is also the largest antibody structure among the five major human isotypes. Spontaneously formed pentamers and hexamers of IgM have avidity effects that could compensate for weaker interactions in monomeric Igs. However, this advantage is counterbalanced by potential steric clashes when binding to multiple large antigens. Recent findings have challenged the expected canonical independence of Fc receptor (FcR) binding at the heavy chain constant (C)-region where the heavy chain C-region isotypes affected antigen binding at the variable (V)-regions, and the variable heavy (VH) families of the V-region affected FcR engagement at the antibody C-regions. With such effects found on other Ig isotypes, IgM candidates need to be investigated with regards to such effects, especially when considering its natural oligomerisation at the C-region that can amplify or modulate such allosteric effects. Methods: Through a panel of 14 recombinant complementarity determining regions (CDRs)-grafted trastuzumab and pertuzumab VH1-7 IgMs subjected to bio-layer interferometry measurements, the interactions with the antigen human epidermal growth factor receptor 2 (Her2), Fc-mu receptor (FcµR), and superantigen Protein L (PpL) were investigated. Results: Significant effects from the V-regions to mitigate FcµR binding and the IgM C-region bidirectional effect modulating Her2 antigen engagements at the V-regions were found. Additional modulatory effects from superantigen PpL binding on the V-region of the kappa chain (Vκ) mitigating antigen binding were also found, revealing possible novel mechanisms of antibody superantigens that can be moderated by the antibody VH frameworks. Conclusions: These findings show that the oligomerisation of IgMs plays a significant role in FcµR, antigen, and superantigen binding that made IgM distinct from the other antibody isotypes and how these features should be considered during further development and protein engineering of IgM therapeutics.

Publication Title

Exploration of Immunology

First Page Number

783

Last Page Number

793

DOI

10.37349/ei.2022.00083

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