User:Immcarle106/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. 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.
 * 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. A challenge in biotherapy is predicting the immunogenic potential of novel protein therapeutics.

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 immune response.


 * Proteins or polysaccharides are used for studies of humoral immune response.
 * Proteins and some lipids/glycolypids 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., Furthermore, immunogenicity data from high-income countries are not always transferable to low-income and middle-income countries. Another challenge is considering how immunogenicity of some vaccinations varying with age.

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 may result in a cellular and humoral immune responses. The therapeutic drug's pharmocokinetics and overall therapeutic effect may be affected by the presence of ADA. The existence of IgG class ADA suggests that T cells participate in this immune response, because antibody isotype switching is a hallmark of T-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 including:


 * Protein structure
 * Synthetic polymers
 * D-amino acids


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

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.