Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Nov;88(11):1447-1457.
doi: 10.1002/prot.25964. Epub 2020 Jul 3.

Conformational changes in a Vernier zone region: Implications for antibody dual specificity

Merve Arslan  1   2 , Dilara Karadag  1 , Sibel Kalyoncu  1
Affiliations

Conformational changes in a Vernier zone region: Implications for antibody dual specificity

Merve Arslan et al. Proteins. 2020 Nov.

Abstract

Understanding the determinants of antibody specificity is one of the challenging tasks in antibody development. Monospecific antibodies are still dominant in approved antibody therapeutics but there is a significant body of work to show that multispecific antibodies can increase the overall therapeutic effect. Dual-specific or "Two-in-One" antibodies can bind to two different antigens separately with the same antigen-binding site as opposed to bispecifics, which simultaneously bind to two different antigens through separate antigen-binding units. These nonstandard dual-specific antibodies were recently shown to be promising for new antibody-based therapeutics. Here, we physicochemically and structurally analyzed six different antibodies of which two are monospecific and four are dual-specific antibodies derived from monospecific templates to gain insight about dual-specificity determinants. These dual-specific antibodies can target both human epidermal growth factor receptor 2 and vascular endothelial growth factor at different binding affinities. We showed that a particular region of clustered Vernier zone residues might play key roles in gaining dual specificity. While there are minimal intramolecular interactions between a certain Vernier zone region, namely LV4 and LCDR1 of monospecific template, there is a significant structural change and consequently close contact formation between LV4-LCDR1 loops of derived dual-specific antibodies. Although Vernier zone residues were previously shown to be important for humanization applications, they are mostly underestimated in the literature. Here, we also aim to resurrect Vernier zone residues for antibody engineering efforts.

Keywords: Vernier zone; antibody; dual specific; human epidermal growth factor receptor 2 (HER2); specificity; vascular endothelial growth factor (VEGF).

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

References

REFERENCES

    1. Eisen HN. Specificity and degeneracy in antigen recognition: yin and yang in the immune system. Annu Rev Immunol. 2001;19:1-21.
    1. Cohn M. Degeneracy, mimicry and crossreactivity in immune recognition. Mol Immunol. 2005;42(5):651-655.
    1. Bostrom J, Haber L, Koenig P, Kelley RF, Fuh G. High affinity antigen recognition of the dual specific variants of herceptin is entropy-driven in spite of structural plasticity. PLoS One. 2011;6(4):e17887.
    1. Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC. Predominant autoantibody production by early human B cell precursors. Science. 2003;301(5638):1374-1377.
    1. Van Regenmortel MH. Specificity, polyspecificity, and heterospecificity of antibody-antigen recognition. J Mol Recognit. 2014;27(11):627-639.

Publication types

MeSH terms

LinkOut - more resources