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PH2501- pharmacology > 35-Biologics > Flashcards

Flashcards in 35-Biologics Deck (28)
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1
Q

What are biologics

A

‘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)
2
Q

RA- basic view

A

-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)

3
Q

How do TNF-a and IL-1b affect the joint

A
  • 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
4
Q

Why target TNF-a

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
5
Q

Anti-TNFa Abs reduce the amount of IL-1b produced by cultures derived from RA synovium

A

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
6
Q

Anti-TNFa Ab (cA2) reduces RA disease activity and assessment

A
  • 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)
7
Q

Anti-TNFa therapy reduces leukocytes traffic in patients

A

-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)

8
Q

Types of Anti-TNFa

A

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)

9
Q

Current anti-TNFa therapeutics

A
  • 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
10
Q

Therapeutic Ab evolution

A
  • Mouse mAbs- 1975
  • Chimeric recombinant Abs- 1984 (Infliximab)
  • CDR grafted Abs- 1987
  • Phage display synthetic Ab- 1992 (Adalimumab)
  • Trangenic human Abs -?- Golimumab
11
Q

Certolizumab- pegol

A
  • 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
12
Q

Technology used for golimumab

A
  • Gene transfer of human Ig genes into mouse
  • Immunisation
  • Human mAb
13
Q

Other targets than TNFa- Abatacept (Orencia)- CLTA4 linked with an Fc

A

-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)

14
Q

Tocilizumab and sarilumab (Anti-IL-6R)

A
  • 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
15
Q

Other uses for anti-TNF drugs

A
  • 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)
16
Q

Side effects and contraindications

A
  • Toxicity- serious infections and sepsis. Injection site reaction, infusion related events e.g. headache, diarrhoea, rash, fever
  • Infliximab is associated with reactivation of TB- whereas the long term effect of TNF-inhibitors on the development of malignancies are still unknown
  • Both infliximab and etanercept are contraindicated in patients with significant cardiac failure
17
Q

Problems with Anti-TNFa therapy

A
  • Improvement is transient (have to keep taking it)
  • Production cost is high
  • Ab or soluble receptors must be injected
  • Abs can be neutralised by patient Abs meaning that the drug no longer works
18
Q

When TNF inhibitors fail NICE technology appraisal TA196

A

-Rituximab in combination with methotrexate is recommended when the patient has severe active RA
AND
-An inadequate response to (DMARDs) including at least 1 tumour necrosis factor inhibitor

19
Q

Rituximab

A
  • (MabThera) is a mAb which binds to CD20- positive B cells. First developed from B cell lymphomas (this only works on immature B cells, so won’t wipe out those that can already produce Abs as these don’t produce CD20)
  • Rituximab ‘labels’ these B cells, which are then killed by CTL (Cytotoxic T lymphocyte)
  • Immature B cells that make useful Abs are also eliminated, but these return after a few months
  • Rituximab is given by IV infusion in a hospital clinic
20
Q

Rituximab

A
  • mAb sticks to the CD20 on the surface of the B cells
  • They are then complementary to macrophages which means that the B cell then gets engulfed
  • Complement-mediated lysis can also occur due to the fact that the mAb is complementary to parts of the complement cascade
  • ADCC: Ab dependant cell-mediated cytotoxicity
21
Q

Rituximab side effects

A
  • Infectious events (Recurrence of latent HepB)
  • Haematological events
  • Pulmonary events (pneumonia, cough)
  • Cardiac and renal toxicity
22
Q

Recommendations

A
  • Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept, all in combination with methotrexate
  • Are recommended as options for treating RA arthritis only if
23
Q

Conditions

A

-Disease is severe that is, a disease activity score (DAS28) greater than 5.1
AND
-Disease has not responded to intensive therapy with a combination of conventional disease-modifying anti-rheumatic drugs (DMARDs)
AND
-The companies provide the drugs as agreed in their patient access schemes

24
Q

Severe methotrexate-naive

A
  • Combining DMARDs is effect
  • so is infliximab and methotrexate
  • Cost and side effects are the determinants
25
Q

Probability of ACR responses in the severe methotrexate naive

A
  • Conventional DMARDs (ACR20=0.56; ACR50=0.32)
  • intensive therapy with a combination of conventional DMARDs (ACR20= 0.76; ACR50= 0.54)
  • The study basically shows you do better with biologics NB but not that much
26
Q

Biosimilars

A
  • Two biosimilar (remsima/inflectra were have been approved as a replacement for infliximab)
  • There are generics for biologics
27
Q

Biosimilars

A
  • Two biosimilar (remsima/inflectra were have been approved as a replacement for infliximab)
  • There are generics for biologics
28
Q

Baricitinib

A

-JAK inhibitors
NB all enzyme inhibitors end in -nib
+ve is that with mAb we have to inject where as these come in oral tablets
+ve cheaper (once patent has run out)
+ve better stability
+ve- we can wash out this where as anti-tnfa we cannot (not certain though)