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Extemp > Andy Watts > Flashcards

Andy Watts Flashcards

1
Q

Therapeutic antibodies are predominantly of what class?

A

IgG1 class

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2
Q

What are antibody-drug conjugates?

A

Antibody attached to a toxic agent.

Antibody is responsible for targeting. Linker is responsible for release. Warhead is responsible for apoptosis.

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3
Q

How are immuno-conjugates and ADC different?

A

Warhead = small cytotoxic molecule = ADC

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4
Q

What is the ADC mechanism of action? [5]

A
  1. ADC attaches to cell surface antigen.
  2. Receptor-mediated endocytosis takes place.
    2a. The drug can be released externally also.
  3. Endosome formation takes place.
  4. Drug is released from the ADC in the lysosome.
  5. The drug is now in the cytosol and can cause: cell death, external release of the drug.
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5
Q

What are the advantages of ADC use? [4]

A
  1. Less off target toxicity effects.
  2. Better tolerated.
  3. Active targeting.
  4. Improved outcomes.
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6
Q

What is Gemtuzumab ozogamicin (GO)?

A

The first ADC approved for use in acute myelogenous leukaemia.

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7
Q

What is Brentuximab vedotin?

A

BV: approved for hodgkins and anaplastic small cell lymphoma.

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8
Q

What is Trastuzumab emtansine?

A

TE: HER2-late-stage/metastatic breast cancer.

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9
Q

What was the first ADC approved?

A

GO: Gemtuzumab ozogamicin.

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10
Q

What ADC is for HER2 breast cancer?

A

Trastuzumab emtansine.

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11
Q

How do first generation ADCs differ from Second generation?

A

1st: conventional chemotherapeutic agents. Not as effective at the intracellular concentrations attainable by ADCs.
2nd: Payloads up to 4000 times more toxic: maytansinoids, auristatins, calicheamicins.

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12
Q

How are maytansinoids effective as ADCs?

A

Inhibit tubulin reorganisation/polymerisation /depolymerisation.
DM1: synthetic maytansinoid used in TE.

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13
Q

Why can unconjugated maytansinoids not be used?

A

Highly toxic. Trees.

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14
Q

How are auristatins effective in as ADCs?

A

Inhibit tubulin reorganisation/polymerisation only.

MMAE: synthetic derivative of dolstatin 10.

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15
Q

Why can unconjugated auristatins not be used?

A

Highly toxic, Sea hare.

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16
Q

What is Adcetris? (BV)

A

Brentuximab vedotin, anti-CD30 mAb conjugated to auristatin

17
Q

Why are anti-CD30 mAb effective?

A

CD30 is associated with anaplastic large cell lymphoma (ALCL) and Hodgkins lymphoma (HL)

18
Q

What is Kadcyla? (TE)

A

Trastuzumab emtansine. Anti-HER2 antibody conjugated to DM-1 payloads.

19
Q

What are ‘immune checkpoints’?

A

Receptors that serve to limit T cell activation. CTLA-4, PD-1.

20
Q

What role do the receptors CTLA-4 and PD-1 play?

A

Receptors that serve to limit T cell activation. CTLA-4, PD-1. ‘Immune checkpoints’

21
Q

What does full T cell activation require?

A

Co-stimulatory signal. CD28 to drive the synthesis of the T cell growth factor IL-2

22
Q

What is the field of immuno-oncology?

A

Aims to allow T cells to mount an effective immune response against cancer.
Cancer cells can overexpress inhibitory receptors on their surface, stopping T cell activation.

23
Q

What are the four major immune checkpoint receptors?

A

CC:
B7
PDL1

TC:
CTLA-4
PD1

24
Q

On which cells are B7 and PDL1 expressed? what is their role?

A

Cancer cells, they are immune check point receptors.

25
Q

On which cells are CTLA-4 and PD1 expressed?

A

T cells.

26
Q

Molecules that block the interaction between which inhibitory receptors and their ligands will allow an immune response?

A
  1. CTLA-4:B7

2. PD1:PDL1

27
Q

What is the ligand for the CTLA-4 receptor?

A

B7 expressed on cancer cells.

28
Q

What is the ligand for the PD1 receptor ?

A

PDL1 expressed by cancer cells.

29
Q

What is Ipilimumab?

A

Anti-CTLA-4 antibody, blocks the interaction between CTLA-4 and B7. It binds to CTLA-4 preventing the binding of B7.

30
Q

What do monoclonal antibodies, antibody-drug conjugates and checkpoints have in common?

A

All are biologicals.

All are expensive.

31
Q

In the manufacture of biologicals what factors should be controlled? [7]

A
  1. Temperature change
  2. Shaking
  3. Oxygen exposure.
  4. Metals.
  5. Filters.
  6. Shearing
  7. Dilution.
32
Q

What surface interactions with containers of biologicals exist?

A

Adsorption.
Leaching.
Silicon: nucleating site.

33
Q

What is the ICH?

A

International Conference for Harmonisation.

Harmonisation of British, US, Japanese and european pharmacopeia.

34
Q

What stability testing guidance exists?

A
  1. Internal NHS guidance.
  2. mAbstalk.com
  3. ICH things.

Extemp (12 decks)

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