| 词条 | Immunogenicity |
| 释义 |
Distinction is made between wanted and unwanted immunogenicity:
Antigenic immunogenic potencyProteins 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.
Protein drugsIn 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.[4] 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. AntigensImmunogenicity is influenced by multiple characteristics of an antigen:
Evaluation methodsIn silico screeningT 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 epitopesDe-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.[5] See also
References{{wiktionary}}1. ^{{cite journal|author=Leroux-Roels G. | title = Vaccine development| url=http://www.sciencedirect.com/science/article/pii/S2210762211000064 | doi=10.1016/j.pervac.2011.05.005 | pmid = 19348557| volume=1 | issue = 4|journal=Perspectives in Vaccinology |pages=115–150| year = 2011}} 2. ^{{cite journal|author1=De Groot A.S. |author2=Scott D.W. | title = Immunogenicity of protein therapeutics | doi=10.1016/j.it.2007.07.011 |pmid=17964218 | volume=28|issue=11 | journal=Trends in Immunology| pages=482–490|year=2007 }} 3. ^{{cite journal|author=Baker M.P.| title = Immunogenicity of protein therapeutics | pmc=3062386 | pmid=21487506| doi=10.4161/self.1.4.13904| volume=1| issue = 4 | date=October 2010| journal=Self Nonself| pages=314–322|display-authors=etal}} 4. ^{{Cite journal|pmc = 3062386|year = 2010|last1 = Baker|first1 = M. P|title = Immunogenicity of protein therapeutics: The key causes, consequences and challenges|journal = Self/nonself|volume = 1|issue = 4|pages = 314–322|last2 = Reynolds|first2 = H. M|last3 = Lumicisi|first3 = B|last4 = Bryson|first4 = C. J|pmid = 21487506|doi = 10.4161/self.1.4.13904}} 5. ^{{cite journal|last=Jawa|first=Vibha|author2=AS Degroot |author3=L Cousens |author4=M Awwad |author5=H. Kropshofer |author6=E. Wakshull |title=T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation|journal=Clinical Immunology|date=December 2013|volume=149|issue=3|doi=10.1016/j.clim.2013.09.006 |pmid=24263283|pages=534–555}}
1 : Immunology |
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