Immunogenicity
Encyclopedia
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 or animal.
The ability of antigen to elicit immune response is called "immunogenicity".
Property of a substance to induce a response in the animal or human body: Antigen
Antigens that do provoke the immune response are "immunogens."
s are significantly more immunogenic than polysaccharide
s. T cell response is required to drive immunogenicity.
Since lipid
s and nucleic acid
s are non-immunogenic hapten
s, they require conjugation
with an epitope
such as a protein or polysaccharide before they can evoke an immunologic response.
Fortunately, 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 a review of immunogenicity determinants, see De Groot and Scott, reference 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. T cells are certainly involved in this immune response when IgG class ADA are observed, 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). Since the impact of immunogenicity can be quite severe, regulatory agencies are developing risk-based guidelines for immunogenicity screening.
One approach is to parse protein sequences into overlapping 9-mer 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 [See De Groot and Martin, Clinical Immunology 2009 reference]. 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.
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
or epitope
Epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
, to provoke an immune response in the body of a human or animal.
Immunogenicity
The ability to induce humoral and/or cell-mediated immune responses.The ability of antigen to elicit immune response is called "immunogenicity".
Property of a substance to induce a response in the animal or human body: Antigen
Antigens that do provoke the immune response are "immunogens."
Immunogenic potency of antigens
ProteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s are significantly more immunogenic than polysaccharide
Polysaccharide
Polysaccharides are long carbohydrate molecules, of repeated monomer units joined together by glycosidic bonds. They range in structure from linear to highly branched. Polysaccharides are often quite heterogeneous, containing slight modifications of the repeating unit. Depending on the structure,...
s. T cell response is required to drive immunogenicity.
Since lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
s and nucleic acid
Nucleic acid
Nucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...
s are non-immunogenic hapten
Hapten
A hapten is a small molecule that can elicit an immune response only when attached to a large carrier such as a protein; the carrier may be one that also does not elicit an immune response by itself...
s, they require conjugation
Conjugate vaccine
A conjugate vaccine is created by covalently attaching a poor antigen to a carrier protein , thereby conferring the immunological attributes of the carrier on the attached antigen...
with an epitope
Epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
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 are frequently immunogenic
In the rush to deliver novel biologics to market, developers have, on occasion, overlooked factors that contribute to protein immunogenicity. In addition, autologous or human-like proteins have proven to be surprisingly immunogenic in some applications, suggesting that assumptions about immune tolerance, too, require careful consideration in biologics design.Fortunately, 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 a review of immunogenicity determinants, see De Groot and Scott, reference 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. T cells are certainly involved in this immune response when IgG class ADA are observed, 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). Since the impact of immunogenicity can be quite severe, regulatory agencies are developing risk-based guidelines for immunogenicity screening.
Factors influencing immunogenicity
- Contribution of antigen to immunogenicity
- Contribution of biological system to immunogenicity
Antigens and immunogenicity
Immunogenicity is influenced by multiple characteristics of an antigen:- Phylogenetic distanceGenetic distanceGenetic distance refers to the genetic divergence between species or between populations within a species. It is measured by a variety of parameters. Smaller genetic distances indicate a close genetic relationship whereas large genetic distances indicate a more distant genetic relationship...
- Molecular size
- EpitopeEpitopeAn epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
density - Chemical composition and heterogeneity
- Protein structure, aa-polymers, GluGlutamic acidGlutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
-LysLysineLysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
, TyrTyrosineTyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
, PhePhenylalaninePhenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form... - Degradability (ability to be processed & presented to T cells)
- D-amino acidAmino acidAmino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s
Methods for evaluating immunogenicity
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 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 [See De Groot and Martin, Clinical Immunology 2009 reference]. 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.