Andy Watts Flashcards
Therapeutic antibodies are predominantly of what class?
IgG1 class
What are antibody-drug conjugates?
Antibody attached to a toxic agent.
Antibody is responsible for targeting. Linker is responsible for release. Warhead is responsible for apoptosis.
How are immuno-conjugates and ADC different?
Warhead = small cytotoxic molecule = ADC
What is the ADC mechanism of action? [5]
- ADC attaches to cell surface antigen.
- Receptor-mediated endocytosis takes place.
2a. The drug can be released externally also. - Endosome formation takes place.
- Drug is released from the ADC in the lysosome.
- The drug is now in the cytosol and can cause: cell death, external release of the drug.
What are the advantages of ADC use? [4]
- Less off target toxicity effects.
- Better tolerated.
- Active targeting.
- Improved outcomes.
What is Gemtuzumab ozogamicin (GO)?
The first ADC approved for use in acute myelogenous leukaemia.
What is Brentuximab vedotin?
BV: approved for hodgkins and anaplastic small cell lymphoma.
What is Trastuzumab emtansine?
TE: HER2-late-stage/metastatic breast cancer.
What was the first ADC approved?
GO: Gemtuzumab ozogamicin.
What ADC is for HER2 breast cancer?
Trastuzumab emtansine.
How do first generation ADCs differ from Second generation?
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.
How are maytansinoids effective as ADCs?
Inhibit tubulin reorganisation/polymerisation /depolymerisation.
DM1: synthetic maytansinoid used in TE.
Why can unconjugated maytansinoids not be used?
Highly toxic. Trees.
How are auristatins effective in as ADCs?
Inhibit tubulin reorganisation/polymerisation only.
MMAE: synthetic derivative of dolstatin 10.
Why can unconjugated auristatins not be used?
Highly toxic, Sea hare.
What is Adcetris? (BV)
Brentuximab vedotin, anti-CD30 mAb conjugated to auristatin
Why are anti-CD30 mAb effective?
CD30 is associated with anaplastic large cell lymphoma (ALCL) and Hodgkins lymphoma (HL)
What is Kadcyla? (TE)
Trastuzumab emtansine. Anti-HER2 antibody conjugated to DM-1 payloads.
What are ‘immune checkpoints’?
Receptors that serve to limit T cell activation. CTLA-4, PD-1.
What role do the receptors CTLA-4 and PD-1 play?
Receptors that serve to limit T cell activation. CTLA-4, PD-1. ‘Immune checkpoints’
What does full T cell activation require?
Co-stimulatory signal. CD28 to drive the synthesis of the T cell growth factor IL-2
What is the field of immuno-oncology?
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.
What are the four major immune checkpoint receptors?
CC:
B7
PDL1
TC:
CTLA-4
PD1
On which cells are B7 and PDL1 expressed? what is their role?
Cancer cells, they are immune check point receptors.
On which cells are CTLA-4 and PD1 expressed?
T cells.
Molecules that block the interaction between which inhibitory receptors and their ligands will allow an immune response?
- CTLA-4:B7
2. PD1:PDL1
What is the ligand for the CTLA-4 receptor?
B7 expressed on cancer cells.
What is the ligand for the PD1 receptor ?
PDL1 expressed by cancer cells.
What is Ipilimumab?
Anti-CTLA-4 antibody, blocks the interaction between CTLA-4 and B7. It binds to CTLA-4 preventing the binding of B7.
What do monoclonal antibodies, antibody-drug conjugates and checkpoints have in common?
All are biologicals.
All are expensive.
In the manufacture of biologicals what factors should be controlled? [7]
- Temperature change
- Shaking
- Oxygen exposure.
- Metals.
- Filters.
- Shearing
- Dilution.
What surface interactions with containers of biologicals exist?
Adsorption.
Leaching.
Silicon: nucleating site.
What is the ICH?
International Conference for Harmonisation.
Harmonisation of British, US, Japanese and european pharmacopeia.
What stability testing guidance exists?
- Internal NHS guidance.
- mAbstalk.com
- ICH things.
