AUTO - B. BIOLOGICS-COVERED Flashcards

1
Q

what is a biologic or biopharmaceutical

A

medicinal product whose synthesis, extraction or manufacture involves living sources (human, animal, microbiological)

includes:
- protein based therapies
- gene and cellular therapies, stem cells, transplantation
- vaccines
- blood products for transfusion
- diagnostic reagents (eg - allergens)

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2
Q

insulin (biologic)

A
  • initial from bovine/porcine pancreas
  • then by recombinant DNA technology to make recombinant proteins for human version of insulin

Replacing endogenous hormone so more selective effect than pig/cow version

but

Injection rather than oral
formulation/stability
risk of immunogenicity (allergic reaction)

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3
Q

protein therapeutics

A

Theralizumab TGN1412 (mAb against CD28 protein on T-cell)

  • anti-CD28 antibody activates T-cells without activation of T-cell receptor (superagonist)
  • low dose in clinical trial
  • immediate adverse effects due to cytokines from activated t-cells (cytokine storm)
  • multiple organ malfunction
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4
Q

Polyclonal antibodies

A
  • many different IgG molecules with high affinity for antigen purified from serum after immunisation
  • interact with different epitopes on the same antigen
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5
Q

Monoclonal antibodies

A
  • IgG producing B-cells isolated from immunised mouse, producing identical IgG molecules
  • interact with a particular epitope on the antigen

*current therapeutic antibodies are monoclonal (-mab)

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6
Q

mechanism of action of antibodies

A
  • bind to receptor (prevent agonist binding) ie - act as antagonist
  • bind to endogenous ligand (prevent it binding to receptor)
  • bind to receptor (activate receptor) ie - act as agonist: autoimmune
  • biphasic antibodies (target immune system eg - to cancer cells)
    bind to 1 protein on immune cell ie natural killer and specific protein on cancer cell
    brings mAb to cancer cell so NK cell can attack cancer cell presenting cancer specific protein
  • direct cytotoxic drug to cancer cell
    mAb bound to cancer-specific protein and then attach cytotoxic drug to other end of Ab
    cytotoxic drug directed more selectively to cancer cell
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7
Q

TNF-alpha blocking

A
  • TNF-alpha is a major cytokine
  • blocking action of TNF-alpha will inhibit inflammation
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8
Q

Anti TNF-alpha therapy

A

Adalinumab (Humira)
- 40 mg sc alternate weeks

Infliximab (Remicade)
- 3mg/kg iv at 2,6,8 weeks

Etanercept (Enbrel)
- 25mg sc twice weekly
(fusion protein so will be broken down quicker)

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9
Q

Targeting IL-6 (cytokine)

A
  • IL-6 binds to soluble IL-6 receptor
  • IL-6 bound IL-6 receptor interacts with gp130 on cell membrane
  • activates inflammation pathways - cytokine storm
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10
Q

Tocilizumab and Sarilumab

A
  • bind to soluble IL-6 receptor
  • prevents binding of IL-6
  • so gp130 not activated and can’t signal transduction
  • used in RA
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11
Q

Tocilizumab - COVID19

A
  • severe COVID infection may lead to cytokine storm
  • due to T-cells/neutrophils driven by IL6 release
  • tocilizumab blocks IL-6 receptor signalling
  • prevents cytokine storm
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12
Q

Siltuximab, Sirukumab, Clazakizumab

A
  • binds to IL-6 to prevent interaction with IL-6 receptor
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13
Q

Olamkicept

A
  • recombinant protein
    extracellular portion of gp130 fused to Fc (constant portion) of a human IgG antibody which binds to IL-6 and prevents it activating gp130
  • binds to IL-6/soluble IL-6 receptor complex to prevent it binding to gp130
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14
Q

Olokizumab

A
  • binds to IL-6 to prevent it binding to gp130
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15
Q

Abatacept - same aa sequence as CTLA-4, recombinant protein

A
  • co-stimulation by binding of MHC complex and CD80/86 protein required for T-cell activation
  • Abatacept blocks CD80/86 binding to CD28
  • fusion protein
  • CTLA-4 analogue which binds to CD80/86 and prevents receptors interacting, T-cell not activated
  • RA
  • not recommended - cost
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16
Q

Biologics in other immune disorders
Ofatumumab, Ocrelizumab, Rituximab

A
  • anti-CD20 antibodies (on B-cells)
  • B-cells play a big role in pathogenesis of MS
  • infiltration of brain by B-cells
  • B-cells produce autoantibodies against myelin sheath (damage to neurones)
  • CD20 is a transmembrane protein on B-cells
  • antibodies bind to CD20 - cross links receptors
  • B-cells recognised by macrophages or NK cills
  • leads to removal go B-cells
  • given every 6 months
  • Rituximab - RA as well
17
Q

Pros of biologics

A
  • increased selectivity for target
  • can bind to target with no known binding site
  • for diseases resistant to current treatments (cytotoxic drugs)
  • long duration of action
18
Q

Cons of biologics

A
  • expensive
  • risk of allergic reaction
  • may be too selective
  • targeting 1 component may not be enough
  • PKs/formulation issues