Biology:Immunogenicity

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Short description: Ability of a foreign substance to provoke an immune response

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:

  • Wanted immunogenicity typically relates to vaccines, where the injection of an antigen (the vaccine) provokes an immune response against the pathogen, protecting the organism from future exposure. Immunogenicity is a central aspect of vaccine development.[1]
  • Unwanted immunogenicity is an immune response by an organism against a therapeutic antigen. This reaction leads to production of anti-drug-antibodies (ADAs), inactivating the therapeutic effects of the treatment and potentially inducing adverse effects.[2]

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 antigen or hapten) to bind specifically with a group of certain products that have adaptive immunity: T cell receptors or antibodies (a.k.a. B cell receptors). Antigenicity was more commonly used in the past to refer to what is now known as immunogenicity, and the two terms are still often used interchangeably. However, strictly speaking, immunogenicity refers to the ability of an antigen to induce 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

T cell epitope content is one of the factors that contributes to 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 monoclonal antibodies (mAbs) are used for several diseases, including cancer and Rheumatoid arthritis.[12] Consequently, the high immunogenicity limited efficacy and was associated with severe infusion reactions. Although the exact mechanism is unclear, it is suspected that the mAbs are inducing infusion reactions by eliciting antibody antigen interactions, such as increased formation of immunoglobulin E (IgE) antibodies, which may bind onto mast cells and subsequent degranulation, causing allergy-like symptoms as well as the release of additional cytokines.[13]

Several innovations in genetic engineering has resulted in the decrease in immunogenicity, (also known as deimmunization), of mAbs. Genetic engineering has led to the generation of humanized and 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. ↑ Leroux-Roels, Geert; Bonanni, Paolo; Tantawichien, Terapong; Zepp, Fred (August 2011). "Vaccine development". Perspectives in Vaccinology 1 (1): 115–150. doi:10.1016/j.pervac.2011.05.005. 
  2. ↑ De Groot, Anne S.; Scott, David W. (November 2007). "Immunogenicity of protein therapeutics". Trends in Immunology 28 (11): 482–490. doi:10.1016/j.it.2007.07.011. PMID 17964218. 
  3. ↑ Baker, Matthew; Reynolds, Helen M.; Lumicisi, Brooke; Bryson, Christine J. (October 2010). "Immunogenicity of protein therapeutics: The key causes, consequences and challenges". Self/Nonself 1 (4): 314–322. doi:10.4161/self.1.4.13904. PMID 21487506. 
  4. ↑ Lindsey, Benjamin B; Armitage, Edwin P; Kampmann, Beate; de Silva, Thushan I (April 2019). "The efficacy, effectiveness, and immunogenicity of influenza vaccines in Africa: a systematic review". The Lancet Infectious Diseases 19 (4): e110–e119. doi:10.1016/S1473-3099(18)30490-0. PMID 30553695. https://eprints.whiterose.ac.uk/143665/1/Influenza%20vaccine%20Africa%20systematic%20review%20-%20Manuscript%20clean%20copy.pdf. 
  5. ↑ Nic Lochlainn, Laura M; de Gier, Brechje; van der Maas, Nicoline; Strebel, Peter M; Goodman, Tracey; van Binnendijk, Rob S; de Melker, Hester E; Hahné, Susan J M (November 2019). "Immunogenicity, effectiveness, and safety of measles vaccination in infants younger than 9 months: a systematic review and meta-analysis". The Lancet Infectious Diseases 19 (11): 1235–1245. doi:10.1016/S1473-3099(19)30395-0. PMID 31548079. 
  6. ↑ Samson, Sandrine I.; Leventhal, Phillip S.; Salamand, Camille; Meng, Ya; Seet, Bruce T.; Landolfi, Victoria; Greenberg, David; Hollingsworth, Rosalind (4 March 2019). "Immunogenicity of high-dose trivalent inactivated influenza vaccine: a systematic review and meta-analysis". Expert Review of Vaccines 18 (3): 295–308. doi:10.1080/14760584.2019.1575734. PMID 30689467. 
  7. ↑ WHO (2014). WHO Expert Committee on Biological Standardization. World Health Organization. ISBN 978-92-4-069262-6. OCLC 888748977. [page needed]
  8. ↑ Dowds, C. Marie; Kornell, Sabin-Christin; Blumberg, Richard S.; Zeissig, Sebastian (1 January 2014). "Lipid antigens in immunity". Biological Chemistry 395 (1): 61–81. doi:10.1515/hsz-2013-0220. PMID 23999493. 
  9. ↑ Stephen, Tom Li; Groneck, Laura; Kalka-Moll, Wiltrud Maria (2010). "The Modulation of Adaptive Immune Responses by Bacterial Zwitterionic Polysaccharides". International Journal of Microbiology 2010: 917075. doi:10.1155/2010/917075. PMID 21234388. 
  10. ↑ Fishman, Jonathan M.; Wiles, Katherine; Wood, Kathryn J. (2015). "The Acquired Immune System Response to Biomaterials, Including Both Naturally Occurring and Synthetic Biomaterials". in Badylak, Stephen F.. Host Response to Biomaterials. Academic Press. pp. 151–187. doi:10.1016/B978-0-12-800196-7.00008-6. ISBN 978-0-12-800196-7. https://books.google.com/books?id=-tucBAAAQBAJ&pg=PA151. 
  11. ↑ 11.0 11.1 11.2 Weber, Constanze A.; Mehta, Preema J.; Ardito, Matt; Moise, Lenny; Martin, Bill; De Groot, Anne S. (30 September 2009). "T cell epitope: Friend or Foe? Immunogenicity of biologics in context". Advanced Drug Delivery Reviews 61 (11): 965–976. doi:10.1016/j.addr.2009.07.001. PMID 19619593. PMC 7103283. https://digitalcommons.uri.edu/cgi/viewcontent.cgi?article=1063&context=immunology_facpubs. 
  12. ↑ Singh, Surjit; Kumar, Nitish K.; Dwiwedi, Pradeep; Charan, Jaykaran; Kaur, Rimplejeet; Sidhu, Preeti; Chugh, Vinay K. (9 October 2018). "Monoclonal Antibodies: A Review". Current Clinical Pharmacology 13 (2): 85–99. doi:10.2174/1574884712666170809124728. PMID 28799485. 
  13. ↑ Schnyder, Benno; Pichler, Werner J. (2009). "Mechanisms of Drug-Induced Allergy". Mayo Clinic Proceedings 84 (3): 268–272. doi:10.4065/84.3.268. PMID 19252115. 
  14. ↑ Doevendans, Erik; Schellekens, Huub (5 March 2019). "Immunogenicity of Innovative and Biosimilar Monoclonal Antibodies". Antibodies 8 (1): 21. doi:10.3390/antib8010021. PMID 31544827. 
  15. ↑ Stryjewska, Agnieszka; Kiepura, Katarzyna; Librowski, Tadeusz; Lochyński, Stanisław (September 2013). "Biotechnology and genetic engineering in the new drug development. Part II. Monoclonal antibodies, modern vaccines and gene therapy". Pharmacological Reports 65 (5): 1086–1101. doi:10.1016/s1734-1140(13)71467-1. PMID 24399705. 
  16. ↑ Lonberg, Nils; Huszar, Dennis (January 1995). "Human Antibodies from Transgenic Mice". International Reviews of Immunology 13 (1): 65–93. doi:10.3109/08830189509061738. PMID 7494109. 
  17. ↑ Pecoraro, Valentina; De Santis, Elena; Melegari, Alessandra; Trenti, Tommaso (June 2017). "The impact of immunogenicity of TNFα inhibitors in autoimmune inflammatory disease. A systematic review and meta-analysis". Autoimmunity Reviews 16 (6): 564–575. doi:10.1016/j.autrev.2017.04.002. PMID 28411169. 
  18. ↑ Kuriakose, Anshu; Chirmule, Narendra; Nair, Pradip (2016). "Immunogenicity of Biotherapeutics: Causes and Association with Posttranslational Modifications". Journal of Immunology Research 2016: 1–18. doi:10.1155/2016/1298473. PMID 27437405. 


Further reading



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