35-Biologics Flashcards
What are biologics
‘Biologics are typically recombinant proteins
- Biologics are developed when small molecules with similar activities have not or cannot be synthesised
- Biologics are especially prominent in treating cancer and chronic inflammation (often in opposite directions)
RA- basic view
-Activated T cell- these activate macrophages
+Activated macrophages produce: IL-6, TNF-a, IL-1
+This produces osteoclasts and chondrocytes which cause inflammation and bone and tissue destruction
+Activated T cells can release cytokines and cause proliferation both aiding inflammation
+Activated T cells can produce activated B cells these produce: Abs and IL-6 and interact with chondrocytes
NB- there are mAbs for IL-1(Anakinra) ,6 (Tocilizumab) and anti-TNF-a (Infliximab) for activated macrophages as well as AntiCD20 to stop B cells (Rituximab)
How do TNF-a and IL-1b affect the joint
- Upregulate cell adhesion molecules on endothelial cells (this increase the trafficking of cells into the joint)
- Stimulate the proliferation of fibroblasts
- Stimulate the synthesis and activation of metallo-proteinases by fibroblasts and chondrocytes
- Promotes bone reabsorption
Why target TNF-a
- Transgenic mice that overexposes TNF-a develop arthritis
- Anti-TNF-a Abs prevent the development of arthritis in mouse molecules
- TNF-a is elevated in the synovial fluid of RA patients
- TNF-a appears to be at the top of the network of pro-inflammatory cytokines. In human joint cell culture, an anti-TNF monoclonal inhibited the production of IL-1,6,8,10 as well as GM-CSF
Anti-TNFa Abs reduce the amount of IL-1b produced by cultures derived from RA synovium
They took synovial cells and run tests putting certain Abs in and measuring IL-1 levels
- When anti-TNFa was placed in after 3 days there was 0 IL-1
- When they placed rabbit IgG and anti-lymphotoxin there were relatively large amounts of IL-1 left
- This is infliximab
Anti-TNFa Ab (cA2) reduces RA disease activity and assessment
- Tender joint count with Ab is reduced
- Swollen joint Ab is reduced
- Pain score is reduced
- Severity of disease is reduced
- CRP levels - are reduced only at higher levels though
- ESR (erythrocyte sedimentation rate)
Anti-TNFa therapy reduces leukocytes traffic in patients
-Fewer granulocytes, T cells, B cells and macrophages are found in the joint
-There is a reduction in chemokines;
+IL-8 (binds CXCR1, recruits neutrophils)
-MCP-1 (binds to CCR2; recruits basophil , monocyte , TH2, TH1)
Types of Anti-TNFa
1) Infliximab: this binds TNFa which is a trimer, so the idea is when TNFa is bound to the Ab it cannot activate the receptor
2) Etanercept: Fc region at the bottom and the extracellular domain of the TNF receptor so TNF can bind to it therefore not react with the actual receptors (however this is not very high affinity because the fact that TNF is a trimer and this only has 2 chains)
Current anti-TNFa therapeutics
- Infliximab: Mouse/human chimeric mAb (disadvantage of mouse mAb, the body can produce Abs against mAb so we lose drug effect)
- Etanercept: ectodomain of TNFR-1 fused to Fc region
- Adalimumab: fully human mAb with phage display complementarity
- Certolizumab pegol: Fab fragment (this is better because we may not want them to activate Fc)
- Golimumab: fully human mAb (made in transgenic mice expressing human Ab L-genes)
- All endorsed with NICE restrictions
Therapeutic Ab evolution
- Mouse mAbs- 1975
- Chimeric recombinant Abs- 1984 (Infliximab)
- CDR grafted Abs- 1987
- Phage display synthetic Ab- 1992 (Adalimumab)
- Trangenic human Abs -?- Golimumab
Certolizumab- pegol
- TNF-a specific Fab fragment of a humanised mAb which has been pegylated
- Evaluated by NICE: technology Guidance TA186, Feb 2010
- Approved to be prescribed with methotrexate in the same way as other TNF inhibitors
Technology used for golimumab
- Gene transfer of human Ig genes into mouse
- Immunisation
- Human mAb
Other targets than TNFa- Abatacept (Orencia)- CLTA4 linked with an Fc
-Infusion in hospital every 2-4 weeks
-Side effects: Similar to other biologics in RA
-Abatacept was initially rejected by NICE as too costly but a price has now been agreed with NHS
-Abatacept modulates the immune response by binding to CD8/86 on APC, such as dendritic cell thus preventing co-stimulatory binding of CD28 on naive T cell and so stopping T cell activation
(CD28 is activating and CTLA4 is inactivating; CLTA4 binds to B7 molecule on the APC)
Tocilizumab and sarilumab (Anti-IL-6R)
- IL-6 cannot bind to receptor alone (it must bind with IL-6 receptor)
- This then binds to gp130 which then drives signal transduction leading to gene expression
- This has to use cytosolic kinases (opposed to having kinases within the receptor domain) called JAK, JAK activates STAT which then enters then nucleus
- Both Tocilizumab and sarilumab both bind to IL-6 receptors preventing signal transduction
- IL-6 is pro-inflammatory so is a benefit in RA
- They can also be used in designer T cells used to attack cancer, instead of relying on TCR you put a Ab instead
- If you activate lots of T cells against tumours you end up with a cytokine explosion, if you knock out IL-6 the patient then become safe again
Other uses for anti-TNF drugs
- Adalimumab and infliximab also recognised for Chron’s disease
- Etanercept, infliximab and adalimumab approved for psoriasis
- Etanercept and adalimumab approved for ankylosing spondylitis (arthritis of the spine)
