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User:Immcarle106/sandbox/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. In other words, immunogenicity is the ability to induce a humoral and/or cell-mediated immune responses.

Distinction is made between wanted and unwanted immunogenicity:

  • Wanted immunogenicity is typically related with vaccines, where the injection of an antigen (the vaccine) provokes an immune response against the pathogen (virus, bacteria), protecting the organism from future exposure. Vaccine development is a complex multi-step process, with immunogenicity being at he center of vaccine efficacy.[1]
  • Unwanted immunogenicity is an immune response by an organism against a therapeutic antigen (ex. recombinant protein, or monoclonal antibody). This reaction leads to production of anti-drug-antibodies (ADAs) inactivating the therapeutic effects of the treatment and, in rare cases, 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]

Antigenic immunogenic potency

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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

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Immunogenicity is influenced by multiple characteristics of an antigen:

  • Degradability (ability to be processed & presented as MHC peptide to T cells)

T cell epitopes

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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 administrated, 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 autoimmmune 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).[12][13]

Monoclonal Antibodies

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Factors affecting Immunogenicity of Monoclonal Antibodies

Therapeutic monoclonal antibodies (mAbs) are used for several diseases, including cancer and Rheumatoid arthritis.[14] The first generation of therapeutic mAbs were of murine (mice) origin, which caused the antibodies to have high immunogenicity, leading to unwanted immunogenic properties.[15] 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.[16]

Several innovations in genetic engineering has resulted in the decrease in immunogenicity, (also known as deimmunization), of mAbs. Genetic engineering has lead to the generation of humanized and chimeric antibodies, by exchanging the murine constant and complementary regions of the immunoglobulin chains with the human counterparts.[17][18]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.[19][20] These findings suggest that other factors, such as glycosylation and route of administration, also affect immunogenicity.[21]

Evaluation methods

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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 a immunotherapy or vaccine will cause unwanted immunogenicity.[22]

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.[23] 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

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References

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Look up immunogenicity in Wiktionary, the free dictionary.
  1. ^ Leroux-Roels G. (2011). "Vaccine development". Perspectives in Vaccinology. 1 (4): 115–150. doi:10.1016/j.pervac.2011.05.005.
  2. ^ De Groot A.S.; Scott D.W. (2007). "Immunogenicity of protein therapeutics". Trends in Immunology. 28 (11): 482–490. doi:10.1016/j.it.2007.07.011. PMID 17964218.
  3. ^ Baker M.P.; et al. (October 2010). "Immunogenicity of protein therapeutics". Self Nonself. 1 (4): 314–322. doi:10.4161/self.1.4.13904. PMC 3062386. 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. ISSN 1473-3099.
  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. ISSN 1473-3099.
  6. ^ Samson, Sandrine I.; Leventhal, Phillip S.; Salamand, Camille; Meng, Ya; Seet, Bruce T.; Landolfi, Victoria; Greenberg, David; Hollingsworth, Rosalind (2019-02-13). "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. ISSN 1476-0584.
  7. ^ WHO. (2014). WHO Expert Committee on Biological Standardization. World Health Organization. ISBN 978-92-4-069262-6. OCLC 888748977.
  8. ^ Dowds, C. Marie; Kornell, Sabin-Christin; Blumberg, Richard S.; Zeissig, Sebastian (January 2014). "Lipid antigens in immunity". Biological chemistry. 395 (1): 61–81. doi:10.1515/hsz-2013-0220. ISSN 1431-6730. PMC 4128234. 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. doi:10.1155/2010/917075. ISSN 1687-918X. PMC 3017905. PMID 21234388.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ "Antigenicity - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2020-02-28.
  11. ^ Weber, Constanze A.; Mehta, Preema J.; Ardito, Matt; Moise, Lenny; Martin, Bill; De Groot, Anne S. (2009-09-30). "T cell epitope: Friend or Foe? Immunogenicity of biologics in context". Advanced Drug Delivery Reviews. Optimizing the Future for Biotechnology Therapies, the Key Role of Protein Engineering. 61 (11): 965–976. doi:10.1016/j.addr.2009.07.001. ISSN 0169-409X.
  12. ^ Weber, Constanze A.; Mehta, Preema J.; Ardito, Matt; Moise, Lenny; Martin, Bill; De Groot, Anne S. (2009-09-30). "T cell epitope: Friend or Foe? Immunogenicity of biologics in context". Advanced Drug Delivery Reviews. Optimizing the Future for Biotechnology Therapies, the Key Role of Protein Engineering. 61 (11): 965–976. doi:10.1016/j.addr.2009.07.001. ISSN 0169-409X.
  13. ^ Weber, Constanze A.; Mehta, Preema J.; Ardito, Matt; Moise, Lenny; Martin, Bill; De Groot, Anne S. (2009-09-30). "T cell epitope: Friend or Foe? Immunogenicity of biologics in context". Advanced Drug Delivery Reviews. Optimizing the Future for Biotechnology Therapies, the Key Role of Protein Engineering. 61 (11): 965–976. doi:10.1016/j.addr.2009.07.001. ISSN 0169-409X.
  14. ^ Singh, Surjit; Kumar, Nitish K.; Dwiwedi, Pradeep; Charan, Jaykaran; Kaur, Rimplejeet; Sidhu, Preeti; Chugh, Vinay K. (2018). "Monoclonal Antibodies: A Review". Current Clinical Pharmacology. 13 (2): 85–99. doi:10.2174/1574884712666170809124728. ISSN 2212-3938. PMID 28799485.
  15. ^ Hwang, William Ying Khee; Foote, Jefferson (2005-05). "Immunogenicity of engineered antibodies". Methods (San Diego, Calif.). 36 (1): 3–10. doi:10.1016/j.ymeth.2005.01.001. ISSN 1046-2023. PMID 15848070. {{cite journal}}: Check date values in: |date= (help)
  16. ^ Schnyder, Benno; Pichler, Werner J. (2009-3). "Mechanisms of Drug-Induced Allergy". Mayo Clinic Proceedings. 84 (3): 268–272. ISSN 0025-6196. PMC 2664605. PMID 19252115. {{cite journal}}: Check date values in: |date= (help)
  17. ^ Doevendans, Erik; Schellekens, Huub (2019-03). "Immunogenicity of Innovative and Biosimilar Monoclonal Antibodies". Antibodies. 8 (1). doi:10.3390/antib8010021. PMID 31544827. {{cite journal}}: Check date values in: |date= (help)CS1 maint: unflagged free DOI (link)
  18. ^ Stryjewska, Agnieszka; Kiepura, Katarzyna; Librowski, Tadeusz; Lochyński, Stanisław (2013-09). "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. {{cite journal}}: Check date values in: |date= (help)
  19. ^ Lonberg, N.; Huszar, D. (1995). "Human antibodies from transgenic mice". International Reviews of Immunology. 13 (1): 65–93. doi:10.3109/08830189509061738. ISSN 0883-0185. PMID 7494109.
  20. ^ Pecoraro, Valentina; De Santis, Elena; Melegari, Alessandra; Trenti, Tommaso (2017-06). "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. ISSN 1873-0183. PMID 28411169. {{cite journal}}: Check date values in: |date= (help)
  21. ^ Bandyopadhyay, Alok (2015). "Complexities of Protein Therapeutics and Immunogenicity". Journal of Bioanalysis & Biomedicine. 07 (03). doi:10.4172/1948-593x.1000126. ISSN 1948-593X.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  22. ^ 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. ISSN 2314-8861. PMC 4942633. PMID 27437405.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  23. ^ Weber, Constanze A.; Mehta, Preema J.; Ardito, Matt; Moise, Lenny; Martin, Bill; De Groot, Anne S. (2009-09-30). "T cell epitope: Friend or Foe? Immunogenicity of biologics in context". Advanced Drug Delivery Reviews. Optimizing the Future for Biotechnology Therapies, the Key Role of Protein Engineering. 61 (11): 965–976. doi:10.1016/j.addr.2009.07.001. ISSN 0169-409X.

Further reading

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  • Immunologists' Toolbox: Immunization. In: Charles Janeway, Paul Travers, Mark Walport, Mark Shlomchik: Immunobiology. The Immune System in Health and Disease. 6th Edition. Garland Science, New York 2004, ISBN 0-8153-4101-6, p. 683–684
  • Descotes Jacques (Mar 2009). "Immunotoxicity of monoclonal antibodies". mAbs. 1 (2): 104–111. doi:10.4161/mabs.1.2.7909. PMC 2725414. PMID 20061816.
  • The European Immunogenicity Platform http://www.e-i-p.eu
  • De Groot AS, Martin W (2009). "Reducing risk, improving outcomes: bioengineering less immunogenic protein therapeutics". Clin Immunol. 131 (2): 189–201. doi:10.1016/j.clim.2009.01.009. PMID 19269256.
  • Porcelli, S. A.; Modlin, R. L. (1999). "The CD1 system: antigen-presenting molecules for T cell recognition of lipids and glycolipids". Annual Review of Immunology. 17: 297–329. doi:10.1146/annurev.immunol.17.1.297. ISSN 0732-0582. PMID 10358761.
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