E3.2

Question 1

Describe Infliximab Mechanism of Action

Answer 1

Binds and neutralizes both soluble and membrane bound TNFa - inhibits further activity
Prevents TNF binding to receptor (TNF2) prevents downstream effects e.g. Initiating transcription of NF-KB signalling

Question 2

Describe Infliximab Other Postulated Mechanism of Action

Answer 2

1. Antibody dependent cell-mediated cytotoxicity (ADCC)
2. Lysis of TNFa-expressing cells through complement (C’) activation
   Infliximab: Bind to membrane bound TNF on Tc - activates complement cascade
   - Complement coats Ab - leads to detection by phagocytes which engulf and break down TNF

Question 3

Name 2 Cytokine blocking agents

Answer 3

Etanercept
- Soluble TNFα receptor fused to Fc domain of human Ig
- binds to and blocks TNFR
- (not recombinant chimeric Ab - instead soluble TNFaR)
Anakinra
- Recombinant human IL-1 receptor antagonist
- Only moderate effectiveness in RA - not often used to treat RA anymore but other autoimmune diseases

Question 4

Describe Targeting T-cells

Answer 4

Tc respond to APCs and expand/differentiate leading to the release of pro-inflammatory mediators
Anti CD80/86-CD28 inhibitor development (Abatacept),
Abatacept is a fusion protein constituted by an Ig fused to the extracellular domain of a cytotoxic T-lymphocyte antigen-4 (CTL4),
It binds with high affinity to the CD80/86 ligand on APCs,
It blocks the interaction between the APC and T-cell
(Adverse effects: hyper sensitivity and anaphylaxis w/ IV administration risk of serious infections (immunosuppressive)

Question 5

Describe Targeting B-cells

Answer 5

B-cells not only give rise to antibody producing plasma cells but are also highly effective APCs,
Anti-CD20 antibody development (Rituximab) – to deplete B cells
Chimeric murine-human monoclonal antibody – binds to the CD20 membrane receptor,
Beneficial when anti-TNF therapy has failed,
Side effects – infusion reaction (30-40% of patients) – consists of headache, fever, rash, hypotension, amongst others

((CD20 is expressed exclusively on B-cells))
Binds to membrane receptor and acts to deplete Bc population
Useful for patients who are autoAb positive

Question 6

Describe Targeted synthetic DMARDs

Answer 6

tsDMARDs – JAK inhibitors (New group of small molecule drugs to target RA)
- Target the Janus-kinase (JAK) pathway,
- Receptor associated intracellular proteins critical for signal transduction from some cytokine receptors,
- IL-2, IL-6 and Interferons.
- Inhibitors - Effective in inflammatory disease by intracellularly blocking tyrosine kinase
(Janus associated kinases)

Question 7

Describe JAK Inhibitors – mechanism of action

2. What are the 2 JAK inhibitors approved for use in RA

Answer 7

Cytokine likely IL-1, IL-6 or TNFa
Ligand binds to R - intracellular Jax kinases are Phosphorylated
Leads to phosphorylation and activation of STAT - signal transducer and activator of transcription pathway
Once P - forms dimers which travel to the cell nucleus & activate transcription process –> inflammation
Blocking affects multiple inflam pathways

2. Tofactinib & Baricitinib

Question 8

Describe Tofactinib

Answer 8

• JAK 1 & 3 inhibitor (little affinity for JAK 2)
• Effective in moderate-severe RA in monotherapy or in combination with methotrexate.
  (efficacy in DMARD naive patients and in patients with insufficient responses to classical DMARDs and even biological DMARDs.
  (Side effects: increased susceptibility to infection, headaches, nausea, hypertension.
  High doses: Deep vein thrombus and pulmonary embolism

Question 9

Describe Baricitinib

Answer 9

AK 1 & 2 inhibitor
- Administered as a monotherapy or in combination with methotrexate.
Side effects??
- Increased cholestrol levels, upper respiratory infections, nausea & increased neutropenia

(administered as a monotherapy or
in combination with methotrexate + similar to our other DMARDs we’ve looked at)