Immunogenicity

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Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted:

A challenge in biotherapy is predicting the immunogenic potential of novel protein therapeutics.[3] For example, immunogenicity data from high-income countries are not always transferable to low-income and middle-income countries.[4] Another challenge is considering how the immunogenicity of vaccines changes with age.[5][6] Therefore, as stated by the World Health Organization, immunogenicity should be investigated in a target population since animal testing and in vitro models cannot precisely predict immune response in humans.[7]

Antigenicity is the capacity of a chemical structure (either an

adaptive immune response. Thus an antigen might bind specifically to a T or B cell receptor, but not induce an adaptive immune response. If the antigen does induce a response, it is an 'immunogenic antigen', which is referred to as an immunogen
.

Antigenic immunogenic potency

Many lipids and nucleic acids are relatively small molecules and/or have non-immunogenic properties. Consequently, they may require conjugation with an epitope such as a protein or polysaccharide to increase immunogenic potency so that they can evoke an immune response.[8]

  • Proteins and few polysaccharides have immunogenic properties, which allows them to induce humoral immune responses.[9]
  • Proteins and some lipids/glycolypids can serve as immunogens for cell-mediated immunity.
  • Proteins are significantly more immunogenic than polysaccharides.[10]

Antigen characteristics

Immunogenicity is influenced by multiple characteristics of an antigen:

  • Phylogenetic distance
  • Molecular size
     :- Molecules having bigger size, particularly those greater than10kDa, will be more immunogenic
  • Epitope density
  • Chemical composition and heterogeneity
  • Degradability (ability to be processed & presented as MHC peptide to T cells)

T cell epitopes

antigenicity. Likewise, T Cell epitopes can cause unwanted immunogenicity, including the development of ADAs. A key determinant in T cell epitope immunogenicity is the binding strength of T cell epitopes to major histocompatibility complexes (MHC or HLA) molecules. Epitopes with higher binding affinities are more likely to be displayed on the surface of a cell. Because a T cell's T cell receptor recognizes a specific epitope, only certain T cells are able to respond to a certain peptide bound to MHC on a cell surface.[11]

When protein drug therapeutics, (as in enzymes, monoclonals, replacement proteins) or vaccines are administered, antigen presenting cells (APCs), such as a B cell or Dendritic Cell, will present these substances as peptides, which T cells may recognize. This may result in unwanted immunogenicity, including ADAs and autoimmune diseases, such as autoimmune thrombocytopenia (ITP) following exposure to recombinant thrombopoietin and pure red cell aplasia, which was associated with a particular formulation of erythropoietin (Eprex).[11]

Monoclonal antibodies

Factors affecting Immunogenicity of Monoclonal Antibodies

Therapeutic

cytokines.[13]

Several innovations in

chimeric antibodies, by exchanging the murine constant and complementary regions of the immunoglobulin chains with the human counterparts.[14][15] Although this has reduced the sometimes extreme immunogenicity associated with murine mAbs, the anticipation that all fully human mAbs would have not possess unwanted immunogenic properties remains unfulfilled.[16][17]

Evaluation methods

In silico screening

T cell epitope content, which is one of the factors that contributes to the risk of immunogenicity can now be measured relatively accurately using in silico tools. Immunoinformatics algorithms for identifying T-cell epitopes are now being applied to triage protein therapeutics into higher risk and low risk categories. These categories refer to assessing and analyzing whether an immunotherapy or vaccine will cause unwanted immunogenicity.[18]

One approach is to parse protein sequences into overlapping nonamer (that is, 9 amino acid) peptide frames, each of which is then evaluated for binding potential to each of six common class I HLA alleles that “cover” the genetic backgrounds of most humans worldwide.[11] By calculating the density of high-scoring frames within a protein, it is possible to estimate a protein's overall “immunogenicity score”. In addition, sub-regions of densely packed high scoring frames or “clusters” of potential immunogenicity can be identified, and cluster scores can be calculated and compiled.

Using this approach, the clinical immunogenicity of a novel protein therapeutics can be calculated. Consequently, a number of biotech companies have integrated in silico immunogenicity into their pre-clinical process as they develop new protein drugs.

See also

References

  1. doi:10.1016/j.pervac.2011.05.005
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  3. PMID 21487506
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  4. S2CID 58767762
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  6. S2CID 59338782
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  7. OCLC 888748977.[page needed
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  8. PMID 23999493
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  9. PMID 21234388
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  10. ISBN 978-0-12-800196-7
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  11. ^
    PMID 19619593
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  12. S2CID 27211386
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  13. PMID 19252115
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  14. PMID 31544827
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  15. PMID 24399705
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  16. PMID 7494109
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  17. PMID 28411169
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  18. PMID 27437405
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Further reading

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