Allotypes

In the context of immunology, allotypes are defined as detectable variations in immunoglobulins in particular constant regions. They differ from idiotypes, which are the unique antigenic markers found on the variable domains of antigen binding receptors. Allotypes exist due to polymorphisms on the genes encoding the immunoglobulin polypeptide chain in the germ line. Therefore, polymorphic epitopes can be found on immunoglobulin constant regions on both heavy and light chains.^1,2

In 1956, allotypes were first identified by ex vivo studies where certain donor sera caused agglutination of erythrocytes treated with human incomplete anti-Rh antibody.2 Now, there are known allotypes on the heavy chains of IgG1, IgG2, IgG3, and IgA2 (G1m, G2m, G3m, A2m allotypes), as well as on the kappa light chains (Km allotypes).^3,4 

Allotypes may be investigated for potential in monoclonal antibody therapeutics because while pathogenic targets can be neutralized by directly binding to antibody variable domains, when they are bound to the constant domain with specialized Fc receptors, this can trigger highly potent inflammatory or anti-inflammatory responses.⁵

Typically, therapeutic antibodies are of the IgG1 isotype. To prevent potential immune reactions, the constant region of the gamma1 chains can be modified by replacing the G1m3 allotype with the G1m17 allotype, which is considered to have lower immunogenicity.⁶

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References: 

1. Goding, J. W. (1996). Genetics of Antibodies. Monoclonal Antibodies, 101–115. https://doi.org/10.1016/B978-012287023-1/50054-7

2. Grubb, R. (1956). Agglutination Of Erythrocytescoated With “Incomplete” Anti-Rh By Certain Rheumatoid Arthritic Sera And Some Other Sera. Acta Pathologica Microbiologica Scandinavica, 39(3), 195–197. https://doi.org/10.1111/J.1699-0463.1956.TB03392.X

3. De Lange, G.G. (1989). Polymorphisms of human immunoglobulins: Gm, Am, Em and Km allotypes. Exp. Clin. Immunogenet. 6, 7-17. 

4. Jefferis, R., & Lefranc, M. P. (2009). Human immunoglobulin allotypes: possible implications for immunogenicity. mAbs, 1(4), 332–338. https://doi.org/10.4161/mabs.1.4.9122

5. Warrender, A. K., & Kelton, W. (2020). Beyond Allotypes: The Influence of Allelic Diversity in Antibody Constant Domains. Frontiers in Immunology, 11, 569371. https://doi.org/10.3389/FIMMU.2020.02016/BIBTEX

6. Lefranc, M. P. (2015). IMGT® Immunoglobulin Repertoire Analysis and Antibody Humanization. Molecular Biology of B Cells: Second Edition, 481–514. https://doi.org/10.1016/B978-0-12-397933-9.00026-6