Immunogenicity Flashcards

1
Q

what is immunogenicity

A

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

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2
Q

what do anti drug antibodies cause

A

cause the biologic to be less effective or can even provoke immunogenicity

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3
Q

what is immunogenicity in the context of biologics

A

an unwanted immune response and must be avoided as much as possible

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4
Q

what are the immune system properties

A
  1. immune tolerance
  2. MHC class II haplotype
  3. patient immunosuppression
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5
Q

what are the immune system physicochemical properties

A
  1. delivery and treatment
  2. manufacturing
  3. storage
  4. formulation
  5. expression system
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6
Q

what can affect immunogenicity

A

effector T cells and regulatory T cells impact immunogenicity
- it is the balance between T effector and Treg cells that control immunogenicity

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7
Q

what is immune tolerance

A

a state in which a T cell can no longer respond to an antigen

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8
Q

what is the role of HLA genes

A
  1. encode MHC II structures that present parts of therapeutic protein peptides on the surface of an APC to a T cell
  2. 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
  3. the population of T effector cells created will induce antibody responses against that therapeutic protein
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9
Q

how are HLA genes associated with immunogenicity

A

because they encode MHCs that bind these immunodominant epitopes very tightly

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10
Q

what does HLA stand for

A

human leukocyte antigen

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11
Q

explain the impact of immunosuppression on immunogenicity

A
  1. if a patient is immunosuppressed due to:
    - age
    - taking immunosuppressive medicine
    - undergoing chemo/radiotherapy
    - HIV
    - Autoimmune disease
  2. there is a high risk of immunogenicity due to their compromised immune system
    - but this doesn’t mean they have no T cells
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12
Q

describe how route of administration affects immunogenicity

A
  1. skin/mucosal surfaces show marked differences compared to blood
    - they have a lot of APCs and extra types of T cells
  2. injecting therapeutic proteins sc or intradermally is more likely to induce immunogenicity
  3. therapeutic proteins are often administered IV if other risk factors are apparent
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13
Q

describe the effect of drug dose, frequency and duration of treatment on immunogenicity

A
  1. short term treatment is less likely to cause an immune response than long term
  2. products given continuously are less likely to be immunogenic than if given intermittently
    - maintenance of trough levels
  3. re-exposure after a long interval is often associated with an enhanced immune response
  4. lower dose of infliximab is more immunogenic than higher dose
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14
Q

give examples of manufacturing issues that may impact immunogenicity

A
  1. 3d structure of mAB- biologic may change during manufacturing process
  2. contaminants- endotoxins, breakdown products
    - can become incorporated into the product
  3. all contaminants can act as adjuvants, altering the immune response to the therapeutic MAB in an uncontrolled manner
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15
Q

describe the issue of aggregation during storage

A
  1. therapeutic mabs are very prone to aggregation which can be caused by manufacturing process/storage
  2. mabs must be carefully stored
  3. aggregated mabs create new epitopes and may become highly immunogenic
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16
Q

what are the 3 main expression systems used

A
  1. bacterial
  2. mammalian cells
  3. transgenic animals
17
Q

describe the characteristics of the bacterial expression system

A

will not link heavy and light antibody chains, so can only be used to provide antibody fragments

18
Q

describe the characteristics of the mammalian cell expression system

A

will express full size, correctly folded, glycosylated IgG at high yield
- fully biologically active
- majority of approved HumAbs expressed in CHO

19
Q

describe the characteristics of transgenic animal expression systems

A

will express full size, correctly folded, biologically active, glycosylated IgG in milk

20
Q

explain how formulation can affect immunogenicity

A
  1. the nature of excipients, buffers and adjuvants used with therapeutic protein can change its structure
  2. 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
21
Q

describe the reactivity to Fab fragment of bDMARDS

A
  1. 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
22
Q

what is anti-idiotype reactivity

A

reaction of immune system to any novel antibody

23
Q

describe the reactivity to Fc fragment of bDMARDS

A
  1. can form immune complexes with the drugs
    - enhance the rate of clearance by scavenging macrophages
  2. ADAs can develop abatacept and etanercept
24
Q

describe what humanisation studies show

A
  1. relationship between successful RA treatment with infliximab/adalimumab and the presence of ADAs
  2. no association between ADAs and clinical response for etanercept, abatacept, certolizumab or golimumab as much lower risk of ADAs being induced
  3. infliximab/adalimumab more immunogenic than other bDMARDs
  4. humanisation is not a universal panacea for preventing immunogenicity
25
Q

outline other factors inducing ADAs during bDMARD therapy

A
  1. high amount of TNF targets at baseline can consume a large proportion of the bDMARD
    - low trough levels of the drug= occurrence of ADAs
  2. use of methotrexate reduced proportion of patients with ADAs by 41%
  3. maintenance of a constant trough level of the biologic is best method for preventing ADA development
  4. temporary withdrawal of treatment favours immunogenicity
  5. obese patients have higher incidence of ADAs
26
Q

how can immunogenicity be tested and predicted

A
  1. 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
  2. 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