Immunogenicity Flashcards
what is immunogenicity
the ability of any molecule to provoke an adaptive immune response
- the outcome of interplay between biological systems and the biophysical/chemical properties of the protein itself
- always mediated by T cells
- such responses are vital to protect from disease or are induced by vaccination
what do anti drug antibodies cause
cause the biologic to be less effective or can even provoke immunogenicity
what is immunogenicity in the context of biologics
an unwanted immune response and must be avoided as much as possible
what are the immune system properties
- immune tolerance
- MHC class II haplotype
- patient immunosuppression
what are the immune system physicochemical properties
- delivery and treatment
- manufacturing
- storage
- formulation
- expression system
what can affect immunogenicity
effector T cells and regulatory T cells impact immunogenicity
- it is the balance between T effector and Treg cells that control immunogenicity
what is immune tolerance
a state in which a T cell can no longer respond to an antigen
what is the role of HLA genes
- encode MHC II structures that present parts of therapeutic protein peptides on the surface of an APC to a T cell
- the MHC II/peptides bind with high affinity to the naive T cell receptor and induce over activation and over proliferation of that T cell
- the population of T effector cells created will induce antibody responses against that therapeutic protein
how are HLA genes associated with immunogenicity
because they encode MHCs that bind these immunodominant epitopes very tightly
what does HLA stand for
human leukocyte antigen
explain the impact of immunosuppression on immunogenicity
- if a patient is immunosuppressed due to:
- age
- taking immunosuppressive medicine
- undergoing chemo/radiotherapy
- HIV
- Autoimmune disease - there is a high risk of immunogenicity due to their compromised immune system
- but this doesn’t mean they have no T cells
describe how route of administration affects immunogenicity
- skin/mucosal surfaces show marked differences compared to blood
- they have a lot of APCs and extra types of T cells - injecting therapeutic proteins sc or intradermally is more likely to induce immunogenicity
- therapeutic proteins are often administered IV if other risk factors are apparent
describe the effect of drug dose, frequency and duration of treatment on immunogenicity
- short term treatment is less likely to cause an immune response than long term
- products given continuously are less likely to be immunogenic than if given intermittently
- maintenance of trough levels - re-exposure after a long interval is often associated with an enhanced immune response
- lower dose of infliximab is more immunogenic than higher dose
give examples of manufacturing issues that may impact immunogenicity
- 3d structure of mAB- biologic may change during manufacturing process
- contaminants- endotoxins, breakdown products
- can become incorporated into the product - all contaminants can act as adjuvants, altering the immune response to the therapeutic MAB in an uncontrolled manner
describe the issue of aggregation during storage
- therapeutic mabs are very prone to aggregation which can be caused by manufacturing process/storage
- mabs must be carefully stored
- aggregated mabs create new epitopes and may become highly immunogenic
what are the 3 main expression systems used
- bacterial
- mammalian cells
- transgenic animals
describe the characteristics of the bacterial expression system
will not link heavy and light antibody chains, so can only be used to provide antibody fragments
describe the characteristics of the mammalian cell expression system
will express full size, correctly folded, glycosylated IgG at high yield
- fully biologically active
- majority of approved HumAbs expressed in CHO
describe the characteristics of transgenic animal expression systems
will express full size, correctly folded, biologically active, glycosylated IgG in milk
explain how formulation can affect immunogenicity
- the nature of excipients, buffers and adjuvants used with therapeutic protein can change its structure
- silicon leaching from a vial closure altered structure of an experimental HIV therapeutic vaccine
- even the infusion diluent and infusion device materials can have an effect
describe the reactivity to Fab fragment of bDMARDS
- Fab fragment of infliximab, adalimumab, golimumab and certolizumab have a neutralising capacity and interfere with binding of antibody to TNFa
- expected with chimeric infliximab and humanised certolizumab
- but not expected with fully human adalimumab and golimumab
what is anti-idiotype reactivity
reaction of immune system to any novel antibody
describe the reactivity to Fc fragment of bDMARDS
- can form immune complexes with the drugs
- enhance the rate of clearance by scavenging macrophages - ADAs can develop abatacept and etanercept
describe what humanisation studies show
- relationship between successful RA treatment with infliximab/adalimumab and the presence of ADAs
- no association between ADAs and clinical response for etanercept, abatacept, certolizumab or golimumab as much lower risk of ADAs being induced
- infliximab/adalimumab more immunogenic than other bDMARDs
- humanisation is not a universal panacea for preventing immunogenicity
outline other factors inducing ADAs during bDMARD therapy
- high amount of TNF targets at baseline can consume a large proportion of the bDMARD
- low trough levels of the drug= occurrence of ADAs - use of methotrexate reduced proportion of patients with ADAs by 41%
- maintenance of a constant trough level of the biologic is best method for preventing ADA development
- temporary withdrawal of treatment favours immunogenicity
- obese patients have higher incidence of ADAs
how can immunogenicity be tested and predicted
- can’t use animal models to predict immunogenicity in humans
- as we are interested in human recombinant proteins, these will almost certainly be immunogenic in any animal - human clinical trials- gold standard to detect and characterise ADAs
- testing in double blind randomised trials
- samples need to be taken for a period after the therapeutic protein has been eliminated
- highest affinity antibodies will be bound to drug first
- trials should continue for 6-12 months to monitor variation in immune responses
