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Biological agents used in autoimmune diseases Flashcards

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1
Q

Describe the structure of antibodies.

A

Antibodies are a Y shaped protein that consists of constant regions (stalk of the Y, also known as the Fc region) and the variable regions (v of the Y, known as the Fab region). At the tip of the Fab region is the hypervariable regions that bind to the antigen.

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2
Q

What are the differing functions between the Fc and Fab regions?

A

The Fc region is responsible for interacting with the Fc receptor on innate immune cells or with C1q, the recognition molecule of the complement system and hence initiates downstream signalling pathways.
Fab region is responsible for antigen binding.

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3
Q

What are the four types of antibody that can be genetically modified?

A

Mouse
Chimeric
Humanised
Fully human antibody

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4
Q

Describe which genetic modifications a chimeric antibody has undergone.

A

A chimeric antibody are molecules made up of two different domains. In application to the human mouse antibody, the Fc portion of the human antibody is combined with the hypervariable (antigen binding portion) region of mouse antibodies.

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5
Q

What are the purpose of chimeric antibodies?

A

There were complications with the use of mouse antibody treatment as when used in humans, they would recognise it as foreign material and immune complex would form. This is known as the human anti-mouse antibody response. By switching the non-antigen binding region to human it reduces this adverse effect without alteration to the binding affinity of the antibody.

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6
Q

Describe the structure of humanised antibodies.

A

Humanised antibodies are human antibodies with the exception of key murine sequences (complementary determining regions) in the hypervariable regions dervied from mouse antibodies which are responsible for the antigen binding.

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7
Q

What is the suffix at the end for drugs that are monoclonal antibodies?

A

-mab

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8
Q

If there is a ‘u’ before the suffix -mab in the drug name what is the type of monoclonal antibody is it?

A

Human

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9
Q

If there is a ‘o’ before the suffix -mab in the drug name what is the type of monoclonal antibody is it?

A

Mouse

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10
Q

If there is a ‘xi’ before the suffix -mab in the drug name what is the type of monoclonal antibody is it?

A

Chimeric

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11
Q

If there is a ‘zu’ before the suffix -mab in the drug name what is the type of monoclonal antibody is it?

A

Humanised

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12
Q

If there is a ‘xi-zu’ before the suffix -mab in the drug name what is the type of monoclonal antibody is it?

A

Hybrid of chimeric and humanised

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13
Q

If there is a ‘im’ before the suffix -mab in the drug name what is the type of disease state is the monoclonal antibody trying to target?

A

Immune

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14
Q

If there is a ‘es’ before the suffix -mab in the drug name what is the type of disease state is the monoclonal antibody trying to target?

A

Infectious disease

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15
Q

If there is a ‘vir’ before the suffix -mab in the drug name what is the type of disease state is the monoclonal antibody trying to target?

A

Viral

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16
Q

If there is a ‘mel’ before the suffix -mab in the drug name what is the type of disease state is the monoclonal antibody trying to target?

A

Melanoma

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17
Q

If there is a ‘col’ before the suffix -mab in the drug name what is the type of disease state is the monoclonal antibody trying to target?

A

Colon

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18
Q

By assessing the name, what type of antibody is Tocilizumab and what is its drug target?

A

Humanised monoclonal antibody and it is an anti-IL-6 so targets the IL-6 receptor.

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19
Q

What is the significance of drugs like Tocilizumab targeting the IL-6 receptor?

A

IL-6 plays a crucial role in inflammation as a pro-inflammatory cytokine. IL-6 stimulates hepatocytes to induce secretion of acute phase proteins such as C-reactive protein, serum amyloid A, fibrinogen. It also stimulates antibody production, induces cytotoxic T cell differentiation but inhibits T reg differentiation.
Tocilizumab binds to both soluble and membrane bound IL-6 receptors and prevents this IL-6 mediated inflammation.

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20
Q

What is the main indication of Tocilizumab?

A

Rheumatoid arthritis (by IV infusion)

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21
Q

By assessing the name, what type of antibody is Rituximab and what is its drug target?

A

Chimeric monoclonal antibody and it targets an antigen (CD20) found on B cells. It appears on immature B cells pre-B lymphocytes but the expression of the antigen increases with the maturity of the B cell.

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22
Q

What is the significance of Rituximab targeting antigens such as CD20 present on B cells?

A

The CD20 antigen is crucial in the cell cycle regulation, apoptosis and calcium signalling. By targeting CD20, rituximab promotes depletion of B cells while sparing cells such as haemopoetic and plasma cells that do not express the CD20 antigen.

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23
Q

What are some of the indications of Rituximab?

A

Rheumatoid arthritis
Non-Hodgkins lymphoma
Chronic lymphocytic leukemia
Pemphigus vulgaris

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24
Q

What type of antibody is Abatacept?

A

Recombinant fusion protein (Fc region is antibody but Fab is recombinant protein)

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25
What is the mechanism of action of Abatacept?
Abatacept contains the human extracellular domain CTLA-4 which is capable to binding to CD80/86 with a higher affinity than it binds to the co-stimulatory molecule CD28. Hence this blocks the co-stimulatory signal required for T cell activation from antigen presenting cells leading to T cell deactivation. This is crucial in application to the immunology of rheumatoid arthritis which is largely linked to T cell activation.
26
What are some of the indications of Abatacept?
Rheumatoid arthritis (moderate to severe) Active psoriatic arthritis
27
What are the receptors that TNF binds to?
TNFR1 and TNFR2
28
What was the first biological DMARDs to be developed?
Anti-TNFa monoclonal antibodies
29
Give some examples of Anti-TNF monoclonal antibodies.
Adalimumab Golimumab Certolizumab Infliximab Etanercept
30
What are some of the roles of TNF-a in inflammation?
Secreted from macrophages and acts on endothelial cells resulting in the production of V-CAM and I-CAM Acts as a growth factor for T and B cells Induces a response against engulfed pathogens Signals for nF-kB to induce the expression of other pro-inflammatory cytokines Stimulates platelet adhesion Regulates haematopoiesis
31
Describe the structure of the monoclonal antibody Infliximab.
Contains the 'xi' after the -mab suffix and hence is chimeric. It has a human Fc region but mouse hypervariable region (region responsible for antigen binding).
32
Describe the structure of the monoclonal antibody Adalimumab.
It is a fully human recombinant monoclonal antibody with both a human Fab and Fc regions.
33
Describe the structure of the monoclonal antibody Golimumab.
Like Adalimumab it is a fully human recombinant monoclonal antibody with both a human Fab and Fc regions.
34
Describe the structure of the monoclonal antibody Etanercept.
A fusion protein containing a human constant region, Fc fused with soluble TNFR2 receptor as the variable region.
35
Describe the structure of the monoclonal antibody Certolizumab.
Unlike other monoclonal antibodies the Fab region of this is humanised whereas the Fc region is instead replaced with a polyethylene glycol moiety.
36
What is the function of PEG moiety instead of the Fc region in Certolizumab?
Prevents complement fixation and antibody mediated cytotoxicity Increases its half life
37
What is a biosimilar?
Highly similar and no clinical meaningful difference but subtle differences in post-modifications patterns.
38
What are the benefits of biosimilars?
Reduces the cost to the NHS- different markets drive the overall cost down meaning that they become more accessible to patients
39
Are the JAK inhibitors monoclonal antibodies?
No they are not monoclonal antibodies however they are targeted therapies and a type of DMARD and are being used in the treatment of auto-immune diseases.
40
What type of drug are JAK inhibitors?
They are tyrosine kinase inhibitors as they inhibit Janus-associated tyrosine kinases JAK1 and JAK3
41
Explain the risk of infections with use of Anti-TNFa therapy?
As TNF is pro-inflammatory cytokine responsible for initiating the immune response to pathogens, by suppressing it this means that the individual is at an increased risk of infection.
42
How does the infection risk change with use of biological therapies?
Anti-TNF antibodies increase the risk of infection by 20% Serious infections can develop such as sepsis, invasive fungal infections, viral and give rise to opportunistic infections Less serious infections (trivial) may be prolonged Infection presentation may be altered (absence of fever)
43
In patients undergoing biological therapy how can the risk of infection be managed (TNF and other biologics)?
Infection mitigation: Patients should not be initiated on to biological therapies when infection is present (this will be picked up on a blood test WBC) - severe infection, requiring antibiotics or hospitalisation Patients should be monitored closely and have diagnostic evaluation completed (source and infective agent) or consider stopping treatment when infection is present Avoid exposure to those with shingles/chickenpox, seek medical treatment if occurs Hold biological for one dosing before surgery unless the risk outweighs the benefit Restart biological at least 14 days after surgery Vaccinations: Patients should ensure they are up to date with vaccines including flu vaccine and pneumococcal Do not receive live vaccines during biological therapy, should not receive at a minimum two but ideally four weeks before Over 50s should receive the Herpes Zooster vaccine before starting treatment If patients have not had chickenpox, should receive Varicella Zooster vaccine before starting therapy
44
Explain the risk of malignancy with use of Anti-TNFa therapy?
TNF has a crucial role in initiating the immune response against mutated and potentially cancer cells and therefore an individual is at an increased risk of malignancy.
45
How does the risk of malignancy with TNF inhibitors compare to that of other biologics?
Increased risk of malignancy with Anti-TNF inhibitors. However remember there is likely to be increased risk of malignancy for some of the conditions that the biologics are being used to treat (increased risk of malignancy associated with Rheumatoid arthritis)
46
In patients undergoing biological therapy how can the risk of malignancy be managed (TNF and other biologics)?
Encourage self monitoring - UV protection for skin cancer Periodic skin examinations? Shouldn't be used if a patient is under investigation for malignancy or have clinical signs of malignancy
47
Can Anti-TNF therapies be used in patients with cardiac failure?
No it is not recommended as it has been shown that when Anti-TNF drugs were used to treat cardiac failure there was increase in severity of symptoms. These patients show a higher levels of TNF.
48
Can biologics (non Anti-TNF antibodies) be used in patients with cardiac failure?
Yes non anti-TNF are okay to use in patients with cardiac failure
49
Aside from cardiac failure are there any other conditions that contra-indicate the use of biologics?
In patients with demyelinating diseases
50
Can patients have alcohol with biologics?
There does not appear to be a significant interaction between alcohol and biological agents however always promote use within the limits and be aware the patients may be on therapies in which restricted use is recommended (conventional DMARDs).
51
When should patients be monitored on biologics?
Before and during biological therapy to establish a baseline, ensure there are no contra-indications and monitor potential adverse effects by referring back to baseline.
52
How should the patient be assessed initially before commencing biological therapy?
Patient should be assessed for any co-morbidities that could contribute to their increased risk of infection or risk of adverse effects, this includes: COPD Renal failure Intestial lung disease (All increased risk of infection)
53
What monitoring parameters should be accounted for in a blood test to establish a baseline in the initial assessment?
FBC (full blood count; WBC, platelets, haemoglobin) Liver function tests- AST, ALT and albumin Renal tests- eGFR, Creatinine Tuberculosis Hepatitis B and C Chest X-ray Additional monitoring may be required for specific drugs or specific diseases
54
If a patient is found to have latent tuberculosis or tests positive for Hepatitis B or C how should this be managed?
The conditions should be treated first or they undergo chemoprophylaxis if latent
55
Once commenced on biological therapy how frequently should therapeutic/toxic monitoring occur?
Every 6 months or if the patient is high risk this should be every 3 months LFT, albumin, FBC and renal function must be taken (This is convenient as it should fall into the monitoring of conventional DMARDs)
56
What is something to consider, if a patient is on multiple DMARDs, conventional and/or biologic when monitoring potential for adverse effects?
Different DMARDs often have the same potential for causing adverse effects (such as bone marrow suppression) therefore it can be difficult to pinpoint which drug is causing which side effect. *Even if a patient has bone marrow suppression after initiating a second DMARD after being stable on Methotrexate for years, the causative agent could potentially be the Methotrexate*.
57
Aside from management of adverse effects what other pharmaceutical care issues are linked to biologics?
It is not appropriate to switch brands of biologics (avoiding switching between biosimilars) unless this is done by the prescriber All patients need to be traceable - brand and batch number as part of the disease registry to ensure follow up Monitoring specific to the drug and disease
58
What is Infliximab indicated for?
Rheumatoid arthritis Crohn's disease Ulcerative colitis Alkylating spondylitis Psoriatic arthritis Psoriasis
59
What preparations does Infliximab come in?
Powder for infusion Pre-filled pen (s/c injection) - best as it can be done at home
60
What is the dosing of Infliximab for rheumatoid arthritis?
3mg.kg at week 0,2,6 then every 8 weeks Alongside Methotrexate which is taken once weekly
61
When should the optimal response of Infliximab occur and what should you do if it doesn't?
About 12 weeks after starting If this does not occur consider increasing the dose or frequency to try and achieve the optimal response. If this still does not occur consider switching the biological agent
62
What is the monitoring required for IV infusion of Infliximab and why?
Infusion should occur over two hours and observe for at a minimum one hour after if not ideally two hours until the patient has stabilised on the therapy. Monitoring is required due to adverse infusion reactions
63
What are some of the potential Infliximab infusion reactions?
Fever Chest pain Hypertension or Hypotension Anaphylactic shock Dyspnoea Oedema Delayed hypersensitivity Pritiuits
64
How should the infusion reactions be treated?
Artificial airways Adrenaline Corticosteroids Antihistamines
65
When is the risk of infusion reactions the greatest?
In the first one to two doses
66
How can the risk of infusion reactions be lowered?
Pre-treatment of paracetamol, antihistamines or corticosteroids. If the patient has experienced an infusion reaction but it is not severe and a decision is made to continue treatment then the rate of the infusion should be lowered.
67
What increases the risk of delayed hypersensitivity for Infliximab?
Increased dosing intervals (longer than 8 weeks), very close monitoring is required If the patient develops antibodies to Infliximab then the increase of 2-3 times of hypersensitivity and results in a reduced duration of response
68
How can the risk of antibody development against Infliximab be managed?
Administration of another immuno-modulator- Methotrexate is recommended to reduce the risk
69
What are the very common side effects of Infliximab?
Infection, in particular upper respiratory tract infections Headaches Infusion related reactions Pain
70
What are the serious side effects associated with Infliximab?
Serious infections or reactivations of latent infections New or worsening of heart failure Delayed hypersensitivity Haematologica reactions Demyelinating disorders Hepatobiliary events Malignancies Serious infusion reactions
71
What are the contra-indications of Infliximab?
Sensitivity to murine proteins Severe infections such as TB, abscesses, opportunistic infections Moderate to severe heart failure
72
When should the use of Infliximab be cautioned?
Chronic/ HX recurrent infection/ immunosuppressive drugs Patients with demyelinating disease Malignancy Mild heart failure Elderly
73
What advise should you give to a patient taking infliximab?
Carry an alert card with you Seek advice for symptoms of TB - persistent cough, weight loss, fever Self-monitor for symptoms of a blood disorder - fever, sore throat, bruising, bleeding Self-monitor for symptoms of delayed hypersensitivity - fever, malaise, pruitis, angio-oedema, wheezing
74
Describe the metabolism of monoclonal antibodies.
Non-specifically metabolised to peptides and amino-acids which are either recycled in the body or excreted via the kidney
75
What is the role of the Pharmacist in administration of biologics?
Checking doses and monitoring Correct indication Correct dose for weight Correct frequency and duration of treatment

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