Immunogenicity

Immunogenicity is the ability of a particular substance, such as an antigen or epitope, to provoke an immune response in the body of a human and 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...) aiming at protecting the organism. Vaccine development is a complex multi-step process, immunogenicity being at the 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]

Antigenic immunogenic potency

Proteins are significantly more immunogenic than polysaccharides. T cell response is required to drive immunogenicity.

Since lipids and nucleic acids are non-immunogenic haptens, they require conjugation with an epitope such as a protein or polysaccharide before they can evoke an immunologic response.

  • Proteins or polysaccharides are used for studies of humoral immune response.
  • Only proteins can serve as immunogens for cell-mediated immunity.

Protein drugs

Protein therapeutics have drastically changed the landscape of treatment for many genetic diseases by providing a drug that is highly specific and lacks many off-target toxicities. The clinical utility of therapeutic proteins has been undermined by the potential development of unwanted immunogenicity against the protein, limiting their efficacy and negatively impacting its safety profile.[4],[5]

Years of thorough study of the parameters influencing vaccine efficacy allow parallels to be drawn for protein therapeutics. Factors including delivery route, delivery vehicle, dose regimen, aggregation, innate immune system activation, and the ability of the protein to interface with the humoral (B cell) and cellular (T cell) immune systems, all impact the potential immunogenicity of vaccine immunogens when delivered to humans (for reviews related to unwanted immunogenicity determinants, see references below).

Like vaccines, protein therapeutics can engender both cellular and humoral immune responses. Anti-drug antibodies (ADA) may neutralize the therapeutic effects of the drug and/or alter its pharmacokinetics. B cells are certainly involved in this immune response when IgG class ADA are observed, because antibody isotype switching is a hallmark of B-dependent antigens.

More serious adverse events can be provoked if ADA cross-react with a critical autologous protein. Examples of adverse ADA responses include autoimmune thrombocytopenia (ITP) following exposure to recombinant thrombopoietin, and pure red cell aplasia, which was associated with a particular formulation of erythropoietin (Eprex). Because the effect of immunogenicity can be severe, regulatory agencies are developing risk-based guidelines for immunogenicity screening.

Antigens

Immunogenicity is influenced by multiple characteristics of an antigen:

  • Phylogenetic distance
  • Molecular size
  • Epitope density
  • Chemical composition and heterogeneity
  • Protein structure, aa-polymers, Glu-Lys, Tyr, Phe
  • Degradability (ability to be processed & presented to T cells)
  • D-amino acids

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.

One approach is to parse protein sequences into overlapping 9-mer (that is, 9 amino acid) peptide frames, each of which is then evaluated for binding potential to each of eight common class II HLA alleles that “cover” the genetic backgrounds of most humans worldwide. 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. Given the resulting “immunogenicity score” of a protein, and taking into consideration other determinants of immunogenicity as described above, it is possible to make an informed decision about the likelihood that a protein will provoke an immune response.

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

T cell epitopes

De-immunization by epitope modification is a strategy for reducing immunogenicity based on disruption of HLA binding, an underlying requirement for T cell stimulation. The idea of rational epitope modification is rooted in the natural process that occurs when tumor cells and pathogens evolve to escape immune pressure by accumulating mutations that reduce the binding of their constituent epitopes to host HLA, rendering the host cell unable to “signal” to T cells the presence of the tumor or pathogen. De-immunized protein therapeutics are now entering the clinic; initial results appear to support this approach to reducing immunogenicity risk. Several methods exist for de-immunization by epitope modification for reduced immunologic potential in-vitro, in-vivo and ex-vivo.[6]

See also

References
  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. Dingman, R.K.; Balu-Iyer, S.V (2018). "Immunogenicity of Protein Pharmaceuticals". Journal of Pharmaceutical Sciences. 108 (5): 1637–1654. doi:10.1016/j.xphs.2018.12.014.
  5. Baker, M. P; Reynolds, H. M; Lumicisi, B; Bryson, C. J (2010). "Immunogenicity of protein therapeutics: The key causes, consequences and challenges". Self/Nonself. 1 (4): 314–322. doi:10.4161/self.1.4.13904. PMC 3062386. PMID 21487506.
  6. Jawa, Vibha; AS Degroot; L Cousens; M Awwad; H. Kropshofer; E. Wakshull (December 2013). "T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation". Clinical Immunology. 149 (3): 534–555. doi:10.1016/j.clim.2013.09.006. PMID 24263283.
  • 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.
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