Immunogenicity
16 important questions on Immunogenicity
What are the 2 major mechanisms of immunogenicity?
2) breakdown of immune tolerance
- the formation of agregates. Here b-cells are stimulated to produce antibodies towards endogenous compounds.
What is the reaction to neo-antigens?
2) The APC will take it up and will show a fragment (peptide) on its MHC.
3) This signal is recognized by a T-helper cell.
4) The T-helper cell will become activated
5) The T-helper cell will activate a B-cell
6) B-cells start to produce antibodies
7) Memory T-cells and memory B-cells are formed.
How does the breakdown of immune-tolerance occur?
They are capable of crosslinking the B-cell receptor when:
- their molecular mass exceeds 100 kDa
- the valency of epitopes (the amount of epitopes that can be recognized by the B-cell) must be more than 10
- the spacing between epitopes is around 5-10 nm.
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Which factors can contribute to the immunogenicity?
- glycosylation
- contaminants and impurities
- formulation
- application route
- dose
- length of the treatment
- assay technology
- patient features
- unknown factors.
In what way the application route can determine immunogenicity induction?
- inhalation: in the lung epithelium are a lot of immune cells.
What are the consequences of immunogenicity?
- antibodies bind to the administered compound. This will result into an altered PK (a shorter half-life) and if binding to the active site occurs as well it will lead to an inactivation of the compound.
For the immune reaction:
- There will be an immunological response; inflammation
- allergic response
- auto-immunity can be developed.
Why do we use large molecules if they can have such severe side effects?
- For certain diseases small molecules cannot help.
- The higher the need for a drug, the more risk will be acceptable.
- it is the biological approach; intervention in existing pathways which uses existing molecules. The replacement of defective or non-present proteins/peptides.
What is the classical example of EPO?
In patients with a destroyed EPO production a chronic anemia is the result. This can be overcome by giving EPO as a medicine.
However, the story goes that once there was a small difference in composition of EPO (formulation difference) due to wrong packaging. Therefore a wrong injection procedure was carried out. This induced an immunogenetic reaction.
It led to autoimmunity of the patients towards EPO and there was nothing there could be done for them. It was lethal.
What are the assay formats that can be used to determine immunogenicity?
- MSD (mesoscale discovery)
- immunoprecipitation
- surface plasmon resonance
What is the direct sandwich ELISA?
- You add the ADA (positive control; you use polyclonal antibodies)
- You add the detection antibody which is labeled with an enzyme e.g.
This one is species specific because the immune response will be polyclonal.
What is the bridging ELISA?
1) The capture antibody is the drug.
2) Then you add your sample (ADA)
3) Then again you add your drug but this time labelled.
The difference is that here the FAB part is used and not the FC part of the antibody.
What is the electrochemiluminescense assay (MSD)?
There is an electrode inside the plate. The more immunological trees the more light will be detected because the detection drug (antibody).
You first coat your plate with a biotin-labeled drug.
then you add the ADA
then you add the sulfo tag labeled drug.
What is the principle of the radioimmune precipitation assay?
2) add radioactive labeled drug.
3) ad protein A that can bind to the antibody. In this way the whole complex will be insoluble and the can centrifuge it and measure the radioactivity.
What is Surface plasmon resonance? (Biacore)
- immobilization of the drug
- addition of sample
- confirmation that the binding is an antibody
- inhibition of the binding with the drug.
This happens under a flow.
The more is added the higher the angle of the light that is reflected. This will be visible in a plot as a peak.
The height of the curve is an indication for the amount of antibody present.
An SPR immunoassay is labelfree unlike ELISA.
However this technique is hardly used anymore.
What is the strategy you use for immunogenicity?
- confirmation: Does the sample have a specific positive signal?
- titration: How much specific is that positive signal?
What are other parameters that you need to take into account regarding to sample storage?
- freeze/thaw
- short term/ long term
- The matrix effect (patient matrix)
1) you might have negative individuals
2) You can overcome this by spiking at a low and a high QC level for all samples.
3) this can be screened and confirmed.
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