biological DMARDs

• Targeted therapies


  Drugs designed specifically to interfere with a specific cytokine OR signalling pathway involved in rheumatic conditions
• Cytokines


  Signalling proteins involved in the regulation of immunity, inflammation, and formation of blood cells
• Examples of cytokines


  • Chemokines
  • Interferons
  • Interleukins (ILs)
  • Lymphokines
  • Tumour necrosis factor (TNF)
• Biologic drugs


  Derived from a biological source using biotechnology processes (e.g. recombinant DNA technology)
• Biologic drugs


  • Large and complex structures
  • Difficult and expensive to produce
• Biologic drugs


  • Monoclonal antibodies (-mabs)
  • Proteins

  
• Monoclonal antibody names


  • -umab (fully human)
  • -omab (mouse)
  • -ximab (chimeric: created by joining of two or more genes from different origins (mouse and human in Infliximab)
  • -zumab (humanised: derived from non-human species but modified to increase their similarity to human antibodies)

  
• Fusion protein


  Made up of two or more proteins fused together
• Pegylated


  Conjugated to polyethylene glycol (PEG). This delays the elimination of the drug and extends its half-life, by reducing renal clearance, protein breakdown, and immunogenicity
• Biologic drugs are reserved for severe cases and for patients in whom csDMARD therapy has failed
• Some biologic drugs are administered in combination with methotrexate (synergistic anti-inflammatory action leads to better therapeutic outcomes and reduced failure rate)
• Biologic drug classes used in rheumatology

  • Tumour Necrosing Factor-Alpha inhibitors
  • Interleukin inhibitors
  • T-cell activation inhibitors
  • B-cell targeting agents
• Tumour necrosis factor (TNF)


  A dominant cytokine involved in the inflammatory process of various rheumatic conditions
• Elevated serum and synovium TNF levels in patients with rheumatic conditions
• TNF controls a network of other inflammatory mediators
• Forms of TNF


  • TNF-α (cachectin) - produced by macrophages
  • TNF-β (lymphotoxin) - produced by lymphocytes
• TNF-α inhibitors


  • Adalimumab
  • Certolizumab Pegol
  • Infliximab
  • Golimumab
  • Etanercept
• Mechanism of action of TNF-α inhibitors

  All TNF-α inhibitors bind to TNF-α, blocking its binding with its receptor, thereby neutralising its biological function
• Fab fragment


  Fragment antigen binding (the region on the antibody that binds to the antigen)

  
• Etanercept


  Made of a TNF receptor fused to the Fc portion of human Immunoglobulin G1. The TNF-alpha receptor part binds to TNF, rendering it inactive. The immunoglobulin part prolongs the serum half-life of the drug.
• Pharmacokinetic properties of TNF-α inhibitors


  • Route of administration
  • tmax
  • F
  • Vd
  • t1/2
• Frequency of administration of maintenance doses for TNF-α inhibitors

  • Adalimumab: every 2 weeks
  • Certolizumab pegol: every 2-4 weeks
  • Golimumab: every month
  • Infliximab: every 8 weeks*
  • Etanercept: once or twice weekly
• Interleukin inhibitors


  Drugs that inhibit the interaction of interleukin with its receptors by binding to specific Interleukin-receptors, preventing the binding of Interleukin (competitive inhibition) or binding to Interleukin itself, neutralising its activity
• Interleukin inhibitors


  • Anakinra
  • Ixekizumab
  • Sarilumab
  • Secukinumab
  • Tocilizumab
  • Ixekizumab
  • Ustekinumab
• Involvement of interleukins in rheumatic diseases

  Pro-inflammatory cytokines involved in inflammatory and immune responses, including those involved in synovial inflammation. Play a key role in joint inflammation and destruction, which is typical of various rheumatologic conditions. Elevated in immune-mediated diseases.
• Interleukins involved in rheumatic diseases

  • IL-1
  • IL-6
  • IL-12
  • IL-17A
  • IL-23
• Mechanism of action of interleukin inhibitors

  • Anakinra: IL-1 receptor antagonist (recombinant version), binds to IL-1 receptor
  • Sarilumab: Monoclonal antibody, binds to IL-6 receptor
  • Secukinumab: Monoclonal antibody, binds to IL-17A
  • Tocilizumab: Monoclonal antibody, binds to IL-6 receptor
  • Ixekizumab: Monoclonal antibody, binds to IL-17A
  • Ustekinumab: Monoclonal antibody, binds to IL-12 and IL-23
• Pharmacokinetic properties of interleukin inhibitors

  • Route of administration
  • tmax
  • F
  • Vd
  • t1/2
• Frequency of administration of maintenance doses for interleukin inhibitors

  • Anakinra: Every day
  • Sarilumab: Every 2 weeks
  • Secukinumab: Every month
  • Tocilizumab SC: Every week
  • Tocilizumab IV: Every 4 weeks*
  • Ixekizumab: Every 4 weeks
  • Ustekinumab: Every 12 weeks
• 1. cell activation inhibitors


  Drugs that inhibit T-cell activation by targeting one of the required signals in T-cell co-stimulation
• Abatacept


  A fusion protein made of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G1

  
• 1. cell activation


  Requires two signals (co-stimulation): 1) recognition of an antigen by the T-cell receptor, 2) binding of CD80 and CD86 proteins on the surface of antigen presenting cells (APCs) to the CD28 receptor on T-cells
• Pharmacokinetic properties of Abatacept

  • Route of administration
  • F
  • Vd
  • t1/2
  • Frequency of administration (maintenance dose)
• Abatacept can be co-administered with biologic immunosuppressive agents, particularly with TNF-inhibitors, in rheumatology
• Antigen Presenting Cells (APCs)

  Cells that interact with CD28 on T-cells
• CD28


  A protein expressed on T-cells, the receptor for CD80 and CD86 proteins
• Mechanism of Action of T-cell Activation Inhibitors

  1. Inhibits T-cell activation by targeting one of the required signals in T-cell co-stimulation

  2. Specifically binds to CD80 and CD86, blocking their interaction with CD28 on T-cells

  3. Results in decreased cell proliferation and decreased cytokine (TNFα, Interleukins) production by T-cells
• Abatacept


  A T-cell activation inhibitor
• Abatacept


  • Binds to CD80 and CD86 on APCs, blocking their interaction with CD28 on T-cells
• Administration and Basic PKs of Abatacept

  • SC injection 125 mg, 78.6% bioavailability, 0.11 L/kg volume of distribution, 14 days half-life, administered weekly
  • IV infusion 500 to 1000 mg, 0.07 L/kg volume of distribution, 13 days half-life, administered every 4 weeks