Clinical Pharmacology II

Question 1

What is the definition of biologicals?

Answer 1

Any pharmaceutical drug product manufactured in, extracted from, or semi-synthesized from biological sources

Question 2

Examples of biologicals (8)

Answer 2

• Vaccines
• Blood/blood components
• Allergenics
• Somatic cells
• Gene therapies
• Tissues
• Recombinant therapeutic proteins
• (Natural) antibiotics

Question 3

Biologicals have a prominent positions in the treatment of …

Answer 3

• (haematological) malignancies
• transplant rejection
• auto-immune disease
• inflammatory disease

Question 4

What are the three modes of action of biologicals?

Answer 4

• Cell surface molecule (cytokine receptor, co-stimulatory molecules)
• Soluble mediator (cytokines, growth factors)
• Receptor blocking

Question 5

Target: cell surface molecule

Answer 5

• Cell elimination
• Receptor blocking

Question 6

Target: soluble mediator

Answer 6

mediator neutralization

Question 7

How does checkpoint inhibition by receptor block work? (7:30)

Answer 7

• PD-L1 binds to PD-1 and inhibits T cell killing of tumor cells
• Blocking PD-L1 or PD-1 allows T cell killing of tumor cell

Question 8

Checkpoint inhibitors interfere with?

Answer 8

co-stimulation phase (signal 2) –> co-inhibitory molecules

Question 9

Examples of biologicals used for transplant rejection + what are their targets?

Answer 9

T cells need to be controlled:
- Muromonab –> CD3
- Basiliximab –> CD25

Question 10

Examples of biologicals used for haematological malignancies + what are their targets?

Answer 10

• Rituximab –> CD20
• Alemtuzumab –> CD25

Question 11

Examples of biologicals used for auto-immune-/inflammatory disease + what are their targets?

Answer 11

• Infliximab –> TNF
• Adalimumab –> TNF

Question 12

Where can the checkpoint inhibitors do their job?

Answer 12

• Priming phase (LN)
• Effector phase (solid malignancies)

Question 13

Why is it convenient for a checkpoint inhibitors to act during the priming phase? + disadvantage of this?

Answer 13

If you give patients the CI, it can act in the LN (where T cell activation happens) , you can get rid of the co-inhibitory pathway

Question 14

Why would they change the structural makeup from mouse to human?

Answer 14

Immunogenicity is lower if you use humanized monoclonals

Question 15

Name the four structures of biologicals? + beschrijf hoe dat er uitziet in een volgende flashcard

Answer 15

• Mouse (-omab)
• Chimera (-ximab)
• Humanised (-zumab)
• Human (-umab)

Question 16

What are the main issues/side effects of biologicals? (2)

Answer 16

• Anti-drug antibodies can cause clearance of biologicals –> loss of response
• Hypersensitivity reaction

Question 17

Which cytokines are released during an hypersensitivity reaction?

Answer 17

TNF-a, IL-6, IL-1

Question 18

Example of a loss-of-response reaction after administration of infliximab?

Answer 18

• Infliximab goes up, then crashes
• Anti-infliximab antibody goes up
• Disease severity increased

Question 19

Therapeutic drug monitoring (TDM):

Answer 19

• Analysis of biologic (trough) level
• Analysis of ADA presence, when indicated

Question 20

Bioavailability of the biologicals depends on.. (4)

Answer 20

• Distribution
• Recycling (FcRn)
• Degradation
• Neutralisation (ADA)

Question 21

What do you have to change if a patient forms anti-biological antibodies??

Answer 21

Switch to other biological

Question 22

How do we detect the in serum troph levels of infliximab and adalimumab?

Answer 22

• Sanquin Biologic Level ELISA
• Theradiag LISA TRACKER ELISA

Question 23

How does the sanquin Biologic Level ELISA work?

Answer 23

• Anti-TNF mAb is bound to the plate
• TNF binds
• Serum of patient biologic binds to TNF
• Secondary antibody/anti-idiotype-biotin –> binds to variable region of any IgG

Question 24

How does the theradiag LISA TRACKER ELISA work?

Answer 24

• TNF bound to plate
• Serum biologic binds to TNF (anti-TNF antibodies of patient)
• Secondary ab/anti-hu-IgG-biotin directed to IgG

Question 25

What is the fundamental assay difference between the Sanquin-ELISA and the Theradiag ELISA?

Answer 25

• Position of serum-biological in the chain. (SQ -Sandwich ELISA - more specific)
• Different secondary antibody (which the LT one binds to all the IgG and the SQ binds to only the variable region of certain ab’s) –> specificity build in

Question 26

What is a bio-similar? What is the big difference with the biological originator?

Answer 26

Structurally related molecule with the same target. Much cheaper.

Question 27

What are the three steps from the psoriasis treatment ladder?

Answer 27

Topical, photo, systemic

Question 28

Drug targets in psoriasis (5)

Answer 28

• IL-12
• IL-17
• IL-22
• IL-23
• TNF-a

Question 28

What is the aim of ‘Therapeutic Drug Monitoring (TDM)’?

Answer 28

Promoting optimum (personalized) drug treatment by maintaining drug concentration within a ‘therapeutic range’

Question 29

What is the main immunosuppressive drug?

Answer 29

Tacrolimus

Question 30

Advantages tacrolimus (3)

Answer 30

• Low incidence of rejection
• Transplantation of other organs is possible

Question 31

Disadvantages tacrolimus (3)

Answer 31

• precious kidney function lost

Question 32

What do CART-T cells work?

Answer 32

Manipulate T cells to recognize or repress specific antigen

Question 33

Describe the effect of betalacept

Answer 33

Blocks both CD80/86 (polyclonal) -> costimulation

Question 34

In what situations can belatacept be used?

Question 35

Name three new forms of immunosuppression

Answer 35

• Anti-IL-6
• Imlifidase
• CAR-T cells

Question 36

What is -omab?

Answer 36

Mouse derived mAb

Question 37

What is -ximab

Answer 37

Chimeric mAb

Question 38

What is -zumab

Answer 38

Humanized mAb

Question 39

What is -umab?

Answer 39

Human mAb