Biologics Flashcards
What does a typical antibody look like?
- Its a ‘Y’ shaped antibody
- Made up of heavy chains and light chains
- There are constant regions within the antibody and variable regions at the tip of the antibody
- The antigen binding sites are at the tips
What are the different types of antibodies?
- Mouse - complete mouse antibody
- Chimeric - The variable regions at the tip have been spliced out and a mouse variable region has been put in
- Humanised - Rather than splicing the whole variable region, you take out and splice in ‘complementary determining regions’, so key sequences within that variable region that are responsible for antigen binding
- Human - fully human antibody
How does Anti-TNFa strategies work?
- In order for TNF to have a function, TNF will bind to a TNF receptor.
- TNF will bind to either TNFR1 or TNFR2
- There is a large family of TNF receptors and many of which have death domains -> leading to apoptosis/cell death
- TNF itself has a main role in inflammation and autoimmune disease
What are the different functions of TNFa?
- Differentiation factor from monocytes to macrophages
- Important cytokine in causing a defence against intracellular pathogens that have been engulfed
- Its a growth factor for T and B cells as they grow sand go through different maturation phases
- Plays a big role in regulating the process haumatopoeisis (formation of blood cellular components)
- TNF signals through transcription factors such as NFkB so by TNF binding to its receptor and signalling through that pathway, it can induce the expression of a range of other cytokines including IL-1, IL-6 etc. hence driving an inflammatory response.
- Can have a pro-thrombotic action, so increasing your platelets sticking together
- It can cause endothelial cells to make them really sticky. So if endothelial cells are activated by TNF, they’ll present on their cell surface a range of different cellular adhesion molecules such as VCAM, ICAM, which allows the endothelial cells to interact with leukocytes within and circulating the blood. If this happens it allows the immune cells to go from the blood and into the endothelial cells and into localised tissues.
As TNF has the capability of inducing inflammatory response by all these roles, it is a target for many inflammatory diseases.
What is biosimilars?
A biosimilar is a biological product, such as monoclonal antibodies, which is highly similar and has no clinically meaningful difference from an existing product.
What other biological agents are available for the treatment of moderate - severe Rheumatoid Arthritis?
- Anti-IL1: Anakinra
- Anti-IL6: Tocilizumab (antibody therapy)
- Anti-costimulation: Abatacept
- Anti-CD20: Rituximab
What are JAK inhibitors?
- JAK stands for Janus Kinases
- These are proteins associated with specific receptors such as receptor tyrosine kinases.
- When you have a growth factor of cytokine signalling, a number of these difference cytokines signal through the JAK stat pathway, which means their tyrosine kinase receptors come together and associated with JAK proteins and once the receptor ligands binds, the JAKs that are associated can phosphorylate the receptor and this then attracts other proteins such as stats that help relay the signal to the nucleus and activate the transcription of other genes e.g. other cytokines hence driving an inflammatory response.
- JAK inhibitors will work through inhibiting the JAK protein associated with the receptor.
- This results in rather than inhibiting one cytokine (e.g. IL-6), your preventing cytokine signalling from a range of different cytokine families
Examples: Tofacitinic and Baricitinib
- Used for RA
Name some Anti-TNF drugs
- Adalimumab
- Certolizumab pegol
- Etanercept
- Golimumab
- Infliximab
Name an IL-6 receptor inhibitor
Tocilizumab
Name an Anti-B-cell
Rituximab
Name an Anti-T-cell
Abatacept
Name some JAK inhibitors
- Tofacitinib
- Baricitinib
What should be monitored when on biologics?
- For co-morbidities
- Full blood count (FBC)
- Renal function (eGFR, Cr)
- Liver function tests (LFTs)
- Test for tuberculosis
- Hepatitis screen (B and C)
- Chest x-ray
Ongoing therapy should be reviewed at least every 6 months.
What should be done in terms of pharmaceutical care when on biologics?
- Patients should remain on their specified brand of treatment unless it is converted under direction of the prescriber.
- Traceability - essential for pharmacovigilance
- Monitoring - specific
What is Infliximab?
Infliximab is an Anti-TNF (TNF inhibitor)
- Infliximab is indicated for RA, Crohn’s disease, Ulcerative colitis etc.
- Infliximab is available as powder for infusion (IV) and pre-filled pen (SC)
IV infusions administration:
- Given over 2 hours and require 1-2 hours observation afterwards
Side effects:
1. Very common S/E
- Infection
- Headache
- IV related reaction
- Pain
- Serious S/E
- Serious infections and reactivations
- New or worsening heart failure
- Delayed hypersensitivity
- Haematological reactions etc
Contraindications:
- Hypersensitivity to other murine proteins
- Severe infection, Tuberculosis, abscesses (collection of pus), opportunistic infections
- Moderate to severe heart failure
Cautions:
- Chronic/Hx recurrent infection/immunosuppressive drugs
- Patients with demyelinating diseases
- Malignancy
- Mild heart failure
- Elderly
