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BIOM30002 - M2M > Lecture 5 - mAbs > Flashcards

Lecture 5 - mAbs Flashcards

1
Q

Which cell type produces Ig and is used in the lab as an ‘Ig producing factory’?

A

Plasma cells

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2
Q

What is a monoclonal antibody?

A

A population of Ab’s from a single B cell clone

i.e., they all have the same specificity

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3
Q

What factors give mAbs great therapeutic potential?

A
  • Well tolerated (come from us)
  • Very high specificity
  • Long-lived
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4
Q

What is the half-life of Ab?

A

Several weeks

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5
Q

Which types of diseases are mAbs mainly used for at the moment?

A
  • Malignancies

* Auto-immune conditions

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6
Q

What are ‘The Big 5’ mAbs?

A
  • Adalimumab (Anti-TNF)
  • Infliximab (Anti-TNF)
  • Trastizumab (Anti-HER2)
  • Bevacizumab (Anti-VEGFA)
  • Rituximab (Anti-CD20)
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7
Q

What is the name of Anti-TNF?

A

Remicade (Infliximab)

Humira (Adalimumab)

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8
Q

What is the name for Anti-CD20?

A

Rituximab

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9
Q

What is the name for Anti-VEGFA?

A

Avastin / Bevacizumab

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10
Q

What is the name for Anti-HER2?

A

Herceptin / Trastuzumab

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11
Q

What recognition did the researchers who came up with mAbs receive?

A

Nobel Prize for Medicine in 1984

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12
Q

Describe the process of harvesting mAbs from mice

A
  1. Mice spleen cells + myeloma cells
  2. Fusion
  3. Hybridomas
  4. Culture in drug
  5. Selection of positive cells
  6. Harvest of mAbs
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13
Q

What are the shortcomings of mAbs from mice?

A
  • They are recognised as foreign and thus have a short half life
  • The ‘mice’ constant region means that they are lacking some effector functions
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14
Q

Describe ‘Humanisation’ of mice mAb

A
  1. CDR grafting in vitro
    • Mouse variable region grafted onto human constant region
    • Ig are fully human apart from the CDRs
    • Longer half life in serum (than fully mouse)
2. Transgenic mice
 • Have human Ig genes
 • Challenge mice with antigen
 • Mice produce human Ig
 • Very good half life
  1. Harvesting from humans
    • Harvest B cells from immune individual
    • Fuse with EBV to immortalise cells
    • Screening to select for the desired specificity
    • Ig isolation
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15
Q

How good are humanised mAbs raised in vitro?

A

Still fairly crude

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16
Q

Describe mAbs raised in transgenic mice

A

Transgenic mice:
• have human Ig genes (C or V & C)

These mAbs are really good because they contain barely any mice parts

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17
Q

Describe mAb generation from humans

A
  1. Infected human with high affinity, IgG
  2. Memory cells collected
  3. Immortalisation: Memory cells infected with EBV
  4. Screening
  5. mAbs harvesting
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18
Q

What are the advantages and disadvantages of mAbs from infected humans?

A

Pros:
• not rejected by patients
• mAbs have specificity that was effective at clearing the infection

Cons:
• Specificities limited to foreign immunogens

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19
Q

What are human mAbs most often used for?

A

Passive immunisation

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20
Q

What are the pros of passive immunisation?

A

Useful when a very quick immune response is needed (HIV, SARS, influenza)

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21
Q

What is ‘naked mAb’ useful for?

A

ADCC: Antibody dependent cell-mediated cytotoxicity
CDC: cell dependent cytotoxicity

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22
Q

What are some ways we can ‘arm’ mAbs?

A 
Multistep targeting:
 • Bispecific mAb
Immunoconjugates:
 • Radioimmunoconjugate
 • Immunocytokine
 • Immunotoxin
 • Immunoliposome
 • Cellular immunoconjugates
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23
Q

Describe Radioimmunoconjugates

A

Radioactive substance conjugates to a mAb which is specific for a tumour cell

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24
Q

Describe Immunocytokines

A

Cytokine conjugated to a mAb specific for a tumour cell

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25
Q

Describe Cellular immunoconjugates

A

mAb bispecific for tumour cell and killer cell

This brings the killer cell right to the tumour cell

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26
Q

What are the mechanisms of action of mAbs?

A
  1. Ligand blockade
  2. Receptor blockade
  3. Target cell depletion
  4. Target cell activation
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27
Q

Which mAb is used against Rheumatoid arthritis, psoriasis & Crohn’s disease?

A

Anti-TNFa:
• Remicade (Infliximab)
• Humira (Adalimumab)

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28
Q

Which mAb is used for anti-angiogenesis and cancer therapy?

A

Anti-VEGFA:

• Avastin (Bevacizumab)

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29
Q

Which mAb is used for Breast cancer?

A

Anti-HER2:

• Herceptin / trastuzumab

30
Q

Which mAb is used for Rheumatoid arthritis and non-Hodgkins lymphoma?

A

Anti-CD20:

• Rituximab

31
Q

Describe the mechanism of action of anti-TNFa

A
  • “Ligand blockade”
  • mAb specific for TNF (pro-inflammatory cytokine)
  • TNF bound by mAb, so it can’t bind to TNF-R on inflammatory cells
32
Q

Describe improvement in Rheumatoid arthritis with Remicade

A

Increased function of joints compared to patients not taking the drug

33
Q

What is the role of TNF-a in Rheumatoid arthritis?

A
  • Strong pro-inflammatory cytokine

* Leads to joint destruction

34
Q

Describe the success of Avastin / Bevacizumab

A

mAb used in cancer, anti-angiogenesis agent

  • Better survival rates compared to conventional therapy
  • However, benefit is not that great
  • Not a cure
35
Q

Describe the function of anti-RANKL mAbs

A

Denozumab

  • “Ligand blockade”
  • Specific for RANKL, which is a factor that increases the action of osteoclasts
  • By blocking RANK-L, we decrease bone resorption in Multiple Myeloma
36
Q

Which cancer cells produce lots of RANK-L?

A

Myeloma cells

37
Q

Where is RANK?

A

Osteoclasts

38
Q

What are some examples of mAb ligand blockade?

A
  • Anti-TNF-α (Adalimumab, Infliximab)
  • Anti-RANK-L (Denosumab)
  • Anti-VEGFA (Bevacizumab)
39
Q

Describe receptor down-modulation

A

When receptors are engaged a lot, they are taken back into the cell and degraded, in order to down regulate the response

40
Q

What are some examples of mAb receptor blockade or down-regulation?

A

Receptor down regulation: Anti-HER2
• HER2 is a receptor in malignant breast cancer cells
• Tumour growth is suppressed by blocking the receptor

41
Q

What is HER-2?

In which disease is it overactive?

A
  • Epidermal GF receptor

* Breast cancer

42
Q

What are some ways that depletion occurs?

A

Anti-CD20
• MAC formation
• ADCC
• Phagocytosis

43
Q

Which cells express CD20?

A

All B cells

44
Q

Describe the action of Rituximab

A
  • mAb specific for CD20

* Brings about transient depletion of ALL B cells

45
Q

Describe the effectiveness of Rituximab

A

50% remission of B cell lymphoma (eg. non-Hogdkins lymphoma) patients

46
Q

What is combination therapy?

A

Conventional treatment + mAb

47
Q

What was Rituximab’s initial use, and what is it used for now?

A

Started off as a cancer therapy

Now used for auto-immune conditions

48
Q

What is Rituximab specific for?

A

CD20

49
Q

What is Herceptin specific for?

A

HER2

aka Trastuzumab

50
Q

What is Remicade specific for?

A

TNFα

aka Infliximab

51
Q

What is Avastin specific for?

A

VEGFA

52
Q

Describe mAbs used for cell activation

What is significant about this?

Give examples

A 
• mAbs specific for parts of T cells
 • When engaged, lead to activation of T cells 
(**T cell activation without antigen!**)
→ 
 • more T cell cytotoxicity
 • more T cell help
eg.
  1. Anti-CD3
  2. Anti-CD28 → this didn’t end well
  3. Anti-CTLA4
53
Q

What happened with the first in man trials of Anti-CD28?

A

Massive cytokine storm and organ failure in the 6 healthy subjects

54
Q

What is Ipilimumab, and what disease is it used for?

A

Anti-CTLA4

Used in metastatic melanoma

55
Q

What is CTLA4?

A

Expressed on the surface of T cells after activation by DCs to prevent further activation

56
Q

What is the effect of Anti-CTLA4?

A

Blockage of inhibition of T cell activation

→ More T cell activation

57
Q

What are some limitations of mAbs as therapeutics?

A
  • Anti-CD28 disaster
  • Cardiotoxicity
  • infections (in immune cell depletions)
  • Anti-mAb antibodies (loss of efficacy)
58
Q

What is an orphan disease?

A

Rare diseases with limited treatment development

59
Q

Describe the structure of CARs

A

Chimeric antigen receptors

  • External Ab ‘for specificity)
  • Intracellular T cell activation section
60
Q

Describe how CARs could be used to treat disease

A

(Chimeric antigen receptor)

  1. T cells isolated from patient
  2. Viral vector delivers anti-CD19 CAR gene to T cells
  3. T cells in culture express anti-CD19 CAR
  4. Lymphocytes killed in patient
  5. CAR expressing T cells reinstated in patient
  6. CAR expressing T cells recognise B cells (through CD19) and induce CTL killing
  7. Depletion of B cells

Used for CLL & Follicular lymphoma

61
Q

How are the CARs put into T cells?

A

Viral vector

62
Q

What is the effect of CAR therapy in B cell cancers?

A

Complete depletion of B cells

63
Q

On which cells is CD19 expressed?

A

All lymphocytes

64
Q

What is IL-1β?

A

Pro-inflammatory cytokine

Brings about systemic features of inflammation:
 • fever
 • pain
 • malaise
 • tissue damage
65
Q

Which diseases is Anti-IL1β used for?
What is the mechanism of action?

How has it been received in patients?

A

Used for CAPS: a collection of rare autoimmune disorders

Mechanism of action:
• Ligand blockade

In patients:
 • Complete response within 7 days
 • Well tolerated
 • Long lasting
 • No side effects
66
Q

What are ‘off-label’ trials?

A

A drug becomes licensed for one rare disease, and then is use in trials for more common diseases.

This is what happened with Rituximab and now for Anti-IL1β mAbs

67
Q

What other disorders is Anti-IL1β being used for?

A

• Juvenile idiopathic arthritis
• Gout
• Late onset Type 2 Diabetes
(chronic inflammatory conditions)

68
Q

Describe the mechanism of B cell depletion with Anti-CD20 (Rituximab)

A

→ mAb binds to CD20

  1. ADCC
    • IgG(1) binds to CD20
    • NK cells bind IgG with IgγR I
    • NK cells induce apoptosis of B cell
2. Complement activation
 • IgM binds to CD20
 • Activation of Cq1
 • Complement cascade
 • Formation of membrane attack complex
3. Phagocytosis
 • Ig binds to CD20
 • Phagocytes binds Ab with FcR
 • Phagocytosis
 • Intracellular killing in phagosome
69
Q

What is the mechanism of action of Anti-VEGFA?

A

Ligand blockade

70
Q

Which class are monoclonal antibodies?

A

IgG1

71
Q

What is the nomenclature for the following:
• Chimaeric mAbs
• CDR grafted (humanised) mAbs
• Fully human mAbs?

A

Chimaeric mAbs: -xi-

CDR grafted (humanised): -zu-

Fully human: -u-

BIOM30002 - M2M (36 decks)

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