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Immune System > 4.1 Monoclonal Antibodies > Flashcards

4.1 Monoclonal Antibodies Flashcards

1
Q

What cells produce antibodies?

A

Plasma cells

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2
Q

What are the 2 main parts of an antibody?

A
  1. Antibody binding fragment

2. Fragment crystallisable region

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3
Q

What is the function of the antibody binding fragment?

A

Recognises antigen. Has hyper variable regions that enable antibodies to recognise a wide range of antigens

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4
Q

What is the function of the fragment crystallisable region?

A

To interact with cell surface receptors on other immune cells to stimulate the immune system (phagocytosis cells)

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5
Q

How do monoclonal antibodies vary from polyclonal antibodies?

A

They are monovalent so have the affinity for a single antigen or epitope

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6
Q

How are monoclonal antibodies used in diagnostics?

A
  • Can be used to tag cell surface markers. By adding certain chemicals to the antibody, this tagging can be visualised by the addition of a light signal which can be read by certain machines such as a flow cytometers or due to the reaction with an enzyme such as in immunohistochemistry
  • used as the basis of reed blood cell grouping as monoclonal antibodies are used to detect RBC antigens
  • used in pregnancy testing as a certain monoclonal antibody can target the antigen pregnancy hormone B-HCG
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7
Q

How have monoclonal antibodies had an impact on therapeutics?

A

G

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8
Q

What are monoclonal antibodies?

A

Monoclonal antibodies are monovalent antibodies which bind to the same epitope and are produced from a single B-lymphocyte clone

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9
Q

What is the hybrids a technique?

A

A technique used to produce specific desired colonial antibodies

  • The generation of hybridomas involves immunising a certain species against a specific epitope on an antigen and then harvesting the B-lymphocytes from the spleen of the mouse
  • 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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10
Q

What are the benefits of monoclonal antibodies?

A
  • specific
  • can be targeted against almost any cell-surface receptor
  • can be produced in large amounts with ease
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11
Q

What are naked monoclonal antibodies?

A

Antibodies that work by themselves and have no other drug or radioactive material attached to them

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12
Q

What are murine monoclonal antibodies?

A

Antibodies derived from another species (mice), not human at all.

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13
Q

What are the disadvantages of murine antibodies?

A

Recognised by the patients immune system as foreign and rapidly cleared and destroyed

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14
Q

What are chimeric antibodies?

A

Antibodies that combined region that remained mouse (murine) integrated with areas of the antibody that were human (65%)

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15
Q

What was the advantage of chimeric antibodies over murine?

A

Chimeric antibodies have the Fc region of the antibody is humanised, the immunogenicity is significantly reduced

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16
Q

What have been the benefits of using fully humanised monoclonal antibodies?

A

The potential for immunogenicity is much lower

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17
Q

What are antibody drug conjugated?

A

Conjugated monoclonal antibodies are where a monoclonal antibody is linked to a potent drug to allow targeted delivery of this potent drug as the antibodies bind to tumour specific antigens. This limits the systemic exposure to the cytotoxic agent
ADCs are designed to allow for the use of highly potent, normally intolerable anti cancer cytotoxic agents

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18
Q

What is the mechanism of action of conjugated monoclonal antibodies?

A
  • monoclonal antibodies bind to specific tumour antigens
  • monoclonal antibodies have the ability to persist in circulation over time, allowing prolonged exposure to the cancer cells and to become internalised by the cancer cell
  • antibody component may be able to prevent signalling by the cancer cell, conduct antibody-dependent cellular cytotoxicity and induct apoptosis
  • receptor mediated endocytosis of the cell receptor and the attached monoclonal antibody occurs
  • lysosomal degradation of the complex occurs
  • release of the potent cytotoxic agent which elicits cell death
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19
Q

How do conjugated monoclonal antibodies target cancers?

A

target antigens are preferentially or exclusively expressed on the surface of cancer cells, not other cells

20
Q

What is the role of linkers in conjugate monoclonal antibodies?

A
  • stable linkers conjugate potent cytotoxic agents to monoclonal antibodies. Linker stability in circulation controls the distribution and delivery of the cytotoxic agent to the target cell
21
Q

What are conjugated monoclonal antibodies used to treat?

A

Treatment of B cell and T cell lymphoma

22
Q

What are bispecific monoclonal antibodies?

A

Utilise the two binding domains of the antibody structure by binding to two different cell populations. This brings the two different cell populations into close proximity with each other

23
Q

What are bispecific monoclonal antibodies currently being developed for?

A

To redirect the immune response against cancer cells by binding to the malignant cancer cell and also a the T cell, bringing the 2 different cells closer together. Leads to T cell effector function against the lymphoma cell

24
Q

What are the 5 different functions of monoclonal antibodies?

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
25
Q

What is antibody-dependent cell-mediated cytotoxicity?

A

When the Fc portion of the antibody binds to the immune effector cells, leading to lysis of phagocytosis of the antigen

26
Q

What are the 2 different broad types of lymphoma?

A

B cell neoplasms

T cell neoplasms

27
Q

What are lymphomas?

A

Clonal proliferation’s of lymphoid cells

28
Q

What is the most common signs and symptoms of a lymphoma?

A 
Enlargement of the lymph nodes
drenching night sweats
fevers
weight loss 
But some have none of these symptoms
29
Q

What are common extra nodal sites of lymphomas?

A 
Spleen
Bone marrow
Liver
Skin
Testes
Bowel
30
Q

What should we do to investigate lymphoma?

A

CT scan
PET CT scan
Tissue biopsy to confirm diagnosis
Immunohistochemistry

31
Q

How does follicular lymphoma appear on biopsy?

A

The lymph node can be taken over by small clonal B lymphocytes which retain the follicular pattern
Slow growing

32
Q

How does a diffuse large B cell lymphoma appear on biopsy?

A

larger clonal B lymphocytes which take over the node in a diffuse pattern
More aggressive and quick growing

33
Q

Which marker is used in immunohistochemistry of lymphomas?

A

CD20 - expressed on B cells

34
Q

What are the treatment strategies for lymphomas?

A
  • Chemotherapy - usually include a steroid treatment as lymphomas are a steroid sensitive blood cancer
  • Radiotherapy - as radiosensitive
  • Monoclonal antibody therapy
  • Emerging new targeted therapy
  • Stem cell transplantation (autologous or allergenic)
35
Q

What is Rituximab?

A

A monoclonal antibody against CD20 on mature B cells

36
Q

What are the side effects of B cell lymphoma?

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 (facial flushing, nausea and vomiting, chest feeling tight)
  • A few people will have severe infusion related reactions as their immune system reacts to the presence of a ’foreign’ protein
37
Q

How do we manage infusion related reactions of monoclonal antibodies?

A

Patient education:
• 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 and prevent the infusion related reaction escalating
• Instruct patient to omit their anti-hypertension medication for 12 hours prior to their infusion.
Prevention with Pre-medication: steroid, anti-histamine, paracetamol
Start at a slow infusion rate, slowly increase if tolerated
Drugs required to treat IRRs should be prescribed prior to starting patients treatment

38
Q

What is tumour lysis syndrome?

A

Occurs following rapid killing of tumour cells in a short period of time, occurs when there is a high tumour burden. Rapid cell death results to release of lots of chemicals such as uric acid that can lead to renal tubular obstruction and failure aswell as major issues with electrolyte imbalances. Can cause hyperkalaemia

39
Q

What monoclonal antibodies are used to treat solid cancers?

A

Trastuzumab – inhibition of HER-2 signalling in breast cancer
Bevacizumab – inhibition of VEG-F signalling stopping angiogenesis
Nivolumumab – inhibition of PV1 signalling

40
Q

What monoclonal antibodies are used in the treatment of autoimmunity?

A

Infliximab and Adalimumab – inhibition of TNF-alpha

41
Q

What monoclonal antibodies are used in the cardiology?

A

Abciximab – inhibition of platelet glycoprotein IIb/IIIa - reducing platelet aggragetion, useful in acute coronary syndromes

42
Q

What monoclonal antibodies are used in the endocrinology?

A

Denosumuab – inhibition of RANK ligand on osteoclasts

43
Q

What is a FAB?

A

antibody binding fragment containing hypervariable regions that allow for recognition of virtually unlimited array of antigens

44
Q

What is the FC region?

A

responsible for binding to the immune effector cells to elicit the immune response. responsible for binding to the immune effector cells to elicit the immune response.

45
Q

What is routinely given pre monoclonal antibody infusion?

A

Paraceptamol
Antihistamines
Steroids
All given to reduce the risk of a hypersensitivity reaction

46
Q

What are the 2 main types of immunisation?

A

Passive: Immediate protection with temporary source of antibody, e.g. Immunoglobulin (Ig’s) and antitoxins
Active: longer term protection leading to the formation of antibodies.

Immune System (4 decks)

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