Immunogenicity
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
- 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
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
- Protein structure
- Synthetic polymers
- D-amino acids
- Degradability (ability to be processed & presented as MHC peptide to T cells)
T cell epitopes
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
Therapeutic
Several innovations in
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
- Vaccines
- Adaptive immune system
- Immunostimulator
- Host cell proteins
References
Further reading
- Immunologists' Toolbox: Immunization. In: ISBN 0-8153-4101-6, p. 683–684
- Descotes, Jacques (March 2009). "Immunotoxicity of monoclonal antibodies". mAbs. 1 (2): 104–111. PMID 20061816.
- The European Immunogenicity Platform http://www.e-i-p.eu
- De Groot, Anne S.; Martin, William (May 2009). "Reducing risk, improving outcomes: Bioengineering less immunogenic protein therapeutics". Clinical Immunology. 131 (2): 189–201. PMID 19269256.
- Porcelli, Steven A.; Modlin, Robert L. (April 1999). "THE CD1 SYSTEM: Antigen-Presenting Molecules for T Cell Recognition of Lipids and Glycolipids". Annual Review of Immunology. 17 (1): 297–329. PMID 10358761.
- Cruse, Julius M.; Lewis, Robert E. (1998). Atlas of Immunology. Boca Raton: CRC Press. ISBN 978-0849394898.