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Semester 4 - immune system > 6. Monoclonal Antibodies > Flashcards

6. Monoclonal Antibodies Flashcards

1
Q

WHat are antibodies?

A

Proteins produced by plasma cells that recognise foreign substances

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2
Q

What is the 2 parts of antibodies?

A
  • Fc portion: Tail region of an antibody, interacts with Fc receptors on immune cells to elicit the immune response.
  • Fab portion: region of the antibody that binds to antigen
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3
Q

What are monoclonal antibodies used for in practise?

A
  • Diagnostics (e.g. blood type, pregnancy test)

- Therapeutics

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4
Q

describe how monoclonal antibodies can be used as a diagnostic in immunohistochemistry

A

by the use of emission of light (fluorescent tag) or an enzymatic reaction (enzymatic tag) to identify specific cells using immunohistochemistry and flow cytometry.

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5
Q

What are monoclonal antibodies?

A

Monovalent antibodies which bind to the same epitope and are produced from a single B-lymphocyte clone which will produce an antibody specific for one particular antigen

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6
Q

What are hybridomas?

A

A hybrid cell used as the basis for the production of antibodies in large amounts for diagnostic or therapeutic use. Hybridomas are produced by injecting a specific antigen into a mouse, collecting an antibody-producing cell from the mouse’s spleen,
• The B-lymphocytes are then fused with an immortal myeloma cell line not containing any other immunoglobulin-producing cells
• The resulting hybridoma cells are then cultured in vitro so only the hybridomas (i.e. the fusion between the primary B-lymphocytes and myeloma cells) survive
• Selected hybridomas are found making a specific desired clonal antibody

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7
Q

What are the different types of naked antibodies?

A
  • Murine (mouse) 0% human (omab)
  • Chimeric 65% human (ximab)
  • Humanised >90% human (zumab)
  • Fully human 100% human (umab)
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8
Q

What are conjugated monoclonal antibodies?

A

Antibodies bound to a cytotoxic (chemo drugs) via stable linkers
- antibodies directly target cancer cells

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9
Q

How are the cytotoxic drugs released from conjugated antibodies?

A

Endocytosis of conjugated antobodies, lysosomal degradation and release of the drug inside the cell

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10
Q

What are bispecific antibodies?

A

Antibodies that can simultaneously bind two separate and unique antigens - target the body’s own immune system (t- cells) to kill target B cells. e.g. can bind to cancerous B cell and normal cytotoxic T cell causing T cell to destroy b cell as they are brought to close proximity

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11
Q

What are the different ways monoclonal antobodies work?

A

• Binding with cell surface receptors to either activate or inhibit signalling within the cell
• Binding to induce cell death
• Binding with cell surface receptors to activate:
- antibody-dependent cell-mediated cytotoxicity (ADCC) or
- complement-dependent cytotoxicity (CDC)
• Internalization (ie being taken in by the cell through the membrane) for antibodies delivering toxins into the cancer cell
• Blocking inhibitory effects on T cells (checkpoints). Thus activating T cells to help ‘kill’ the cancer cells

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12
Q

What CDs are markers for B and T cells?

A

B cells: 19, 20

T cells: 3, 4, 8

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13
Q

What type of cancer is lymphoma?

A

Clonal proliferations of lymphoid cells

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14
Q

What are the 2 main divisions of lymphomas?

A

Divided into B and T cell neoplasms

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15
Q

What do lymphomas typically cause?

A

It typically causes enlargement of lymph nodes

- also extra nodal involvement

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16
Q

What extra nodal involvements occur in lymphomas?

A

The spleen, bone marrow and other areas of the body such as liver, skin, testes and bowel (‘extra-nodal’) may also be involved

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17
Q

What do patients with lymphomas typically complain of?

A

drenching night sweats, fevers and weight loss .. But some have none of these symptoms

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18
Q

What are 2 types of b cell lymphoma?

A
  • follicular lymphoma

- diffuse large B cell lymphoma

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19
Q

What is follicular lymphoma?

A

Lymph node can be taken over by small clonal B lymphocytes which retain the follicular pattern Follicular lymphoma
- slow-growing type of non-Hodgkin lymphoma

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20
Q

What is diffuse large B cell lymphoma?

A

larger clonal B lymphocytes which take over the node in a diffuse pattern
- more aggressive non-hodgkins

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21
Q

what is the main CD marker for B cells

A

CD20

22
Q

What are the treatment strategies in lymphoma?

A
  • Chemotherapy
  • Radiotherapy - more used for localised disease or symptom relief in palliative care
  • Monoclonal antibody therapy
  • Emerging new targeted therapy
  • Stem cell transplantation
23
Q

give an example of a monoclonal antibody against CD20

A

rituximab

24
Q

WHat are the side effects of monoclonal antibodies?

A
  • Some have no or mild symptoms eg mild fatigue
  • Many have a mild reaction to the 1st infusion and then tolerate subsequent treatments well
  • A few people will have severe infusion related reactions as their immune system reacts to the presence of a ‘foreign’ protein
25
Q

What is important to tell patients before monoclonal therapy?

A
  • Explain to the patient that even though they have received premedication, they may still experience some side effects.
  • Explain that they should inform staff the moment of any change, so that staff can take immediate action
  • Instruct patient to omit their anti-hypertension medication for 12 hours prior to their infusion.
26
Q

How mught infusion related reactions be prevented?

A

Prevention with Pre-medication: steroid, anti-histamine, paracetamol
Start at a slow infusion rate, slowly increase if tolerated

27
Q

what syndrome can trials for monoclonal antibodies to treat cancer cause?

A

tumour lysis syndrome - rapid breakdown of tumour leading to rapid increase in creatinine and may also cause hyperkalaemia

28
Q

Give examples of monoclonal antibodies used to treat solid cancers?

A
  • Trastuzumab - inhibition of HER-2 signalling
  • Bevacizumab - inhibition of VEG-F signalling
  • Ipilimumab - inhibition of CTLA-4 signalling
  • Nivolumumab - inhibition of PD1 signalling
29
Q

Give examples of monoclonal antibodies used to treat autoimmunity

A

• Infliximab and Adalimumab - inhibition of TNF-alpha

30
Q

Give examples of monoclonal antibodies used to treat cardiology and endocrine diseases

A
  • Abciximab – inhibition of platelet glycoprotein IIb/IIIa

* Denosumuab – inhibition of RANK ligand on osteoclasts

31
Q

what does Antibody binding with cell surface receptors that can activate or inhibit cell signalling result in?

A
  • Cell death induction
  • Antibody dependent cell mediated toxicity (ADCC) activation
  • Complement dependent cytotoxicity (CDC) activation
32
Q

list 5 diseases that Monoclonal antibodies can be used for?

A
  • Lymphoma
  • Solid cancers
  • Autoimmune disease
  • Cardiology
  • Endocrine
33
Q

how are lymphomas diagnosed?

A

Diagnosis is diagnosed via biopsy and histochemistry. Lymphomas can be diagnosed via structure and use of CD20 immunohistochemistry to diagnose B cell lymphoma.

34
Q

what is rheumatoid arthritis?

A

an autoimmune disease associated with autoantibodies to the Fc portion of immunoglobulin G (rheumatoid factor) and to citrullinated cyclic peptide.

35
Q

pathophysiology of rheumatoid arthritis

A

There is persistent synovitis, causing chronic symmetrical polyarthritis with systemic inflammation. Patients can develop a range of non-articular problems affecting many systems of the body.

36
Q

how does RA typically manifest?

A

as a progressive, symmetrical, peripheral polyarthritis, evolving over a period of a few weeks or months in patients between 30 and 50 years of age, although the disease can occur at any age

37
Q

what causes synovial disease in rheumatoid arthritis?

A

RA is primarily a synovial disease, and synovitis occurs when chemoattractants produced in the joint recruit circulating inflammatory cells. Over-production of tumour necrosis factor alpha (TNF-α) leads to synovitis and joint destruction.

38
Q

what drives the overproduction of TNF-α?

A

Interaction of macrophages and T and B lymphocytes drives this over-production.

39
Q

what is the action of TNF-α?

A

TNF-α stimulates over-production of IL-6, as well as other cytokines

40
Q

what can be targeted to treat synovitis in RA?

A

Blockade of TNF-α and IL-6 has produced marked improvement in synovitis and systemic malaise, indicating the pivotal role of these cytokines in the chronic synovitis

41
Q

how does RA affect the lungs?

A

can cause rheumatoid nodules of the lungs - epithelia histiocytes surrounding necrotic tissue but not infection

42
Q

in suspected rheumatoid nodules of lungs, what investigations should be done?

A

xray
CT
FBC

43
Q

what is d dimer?

A

D-dimer is a fibrin degradation product containing two cross-linked D domains released by the action of plasmin

44
Q

what is the d dimer test?

A

The level of d-dimers can be used to assess the extent of clotting.
The d -dimer test is a blood-based assay that uses antibodies to the d -dimer protein to measure the presence or level of circulating d -dimer.

45
Q

what does an elevated d dimer test indicate?

A

Elevated levels are associated with elevated fibrin or clot somewhere in the body. Unfortunately, elevated d -dimer can occur in a variety of conditions other than acute Pulmonary embolism and DVT, most notably malignancy, pregnancy (particularly later trimesters), chronic inflammatory conditions, recent surgery, infection, stroke, myocardial infarction, and even advanced age.

46
Q

what does a negative d dimer test indicate?

A

A negative test is helpful in ruling out a Pulmonary embolism or other significant clot.

47
Q

what may cause bilateral feet swelling?

A

If the kidney loses protein in the urine (rather than keeping it in the blood) then the level of albumin in the blood will fall and the oncotic pressure in blood vessels will fall and fluid will leak out of the blood vessels into the surrounding tissue.

heart failure

48
Q

what is serum creatinine measured for?

A

Serum creatinine is an important indicator of renal health because it is an easily measured byproduct of muscle metabolism that is excreted unchanged by the kidneys. If the filtration in the kidney is deficient, creatinine blood levels rise. A rise in blood creatinine level is a late marker, observed only with marked damage to functioning nephrons.

49
Q

what does a fall in GFR indicate?

A

kidney and glomerulus is not working properly

50
Q

what is the pathogenesis of systemic lupus Erythematosus

A
  • When cells die by apoptosis, the cellular remnants appear on the cell surface as small blebs that carry self antigens.
  • These antigens include nuclear constituents (e.g. DNA and histones), which are normally hidden from the immune system.
  • In people with SLE, removal of these blebs by phagocytes is inefficient, so that they are transferred to lymphoid tissues, where they can be taken up by antigen- presenting cells.
  • The self antigens from these blebs can then be presented to T cells, which in turn stimulate B cells to produce autoantibodies directed against these antigens.
51
Q

what does The combination of availability of self antigens and failure of the immune system to inactivate B cells and T cells that recognise self antigens (i.e. a breakdown of tolerance) in SLE lead to?

A
  • Development of autoantibodies that either form circulating complexes or deposit by binding directly to tissues.
  • Activation of complement and influx of neutrophils, causing inflammation in those tissues.
  • Abnormal cytokine production
52
Q

what causes Systemic lupus erythematosus nephritis (lupus nephritis)

A

Immune deposits in the glomeruli and mesangium are characteristic of SLE and stain positive for IgG, IgM, IgA and the complement components C3, C1q and C4 on immunofluorescence. - lead to inflammation and damage to glomeruli

Semester 4 - immune system (6 decks)

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