Lecture 11 ( Drug Development 2 - Drug discovery)

Question 1

Name an example of one of the growing biologics-based drug treatments?

Answer 1

Monoclonal antibodies

Question 2

What is an advantage of biopharmaceuticals?

Answer 2

Off-target toxicology uncommon

Question 3

What are the two main reasons to withdraw drugs? (2)

Answer 3

-Causes risk to patients
-Lack of demand

Question 4

How is safety tested in drug (Phase 1)?

Answer 4

Groups divided into smaller groups called cohorts, cohort gets low doses, slowly increasing until best tolerated dose found (also tested on animals)

Question 5

What properties are needed in a lead compound? (3)

Answer 5

-Must bind selectively to receptor site
-Musts elicit desired response from receptor
-Sufficient bioavailability

Question 6

What are the differences in weight, origin, and structure for? (3)

-Small molecule
-Biological molecule
-Monoclonal antibody

Answer 6

1. Small molecule
   -Low molecular weight
   -Chemically synthesised
   -Well defined structure.
2. Biological molecule
   -High molecular weight
   -Derived from living organisms
   -Large and complex structure
3. Monoclonal antibody
   -High molecular weight
   -Derived from living organisms
   -More complex structure

Question 7

What is immunotherapy?

Answer 7

Immunotherapy is a form of cancer treatment that uses the immune system to attack cancer cells, in much the same way that it attacks bacteria or viruses.

Question 8

What are the two types of immunotherapies and how do they work? (4)

Answer 8

Checkpoint Inhibitors
Releasing a natural brake on your immune system so that immune cells called T cells recognize and attack tumours.

CAR T Cell Therapy
Chimeric antigen receptor (CAR) T cell therapy, genetically engineer a patient’s own immune cells to make a new protein. This turns them into supercharged cancer fighters.

Question 9

How does CAR T Cell Therapy work? (3)

Answer 9

-CD19 blood cells extracted from patient

-You modify with integrated plasmid into cells to transfect them

-Fusion of receptor protein with monoclonal antibody, which puts receptor on t cell that will start destroying cancer

Question 10

What is a risk of CAR T Therapy?

Answer 10

Could cause cytokine-release syndrome (CRS) which is massive/rapid release of cytokine which causes fevers and drop in blood pressure

Question 11

What is a biopharmaceutical?

Answer 11

Biopharmaceuticals defined as products where the active substance is produced/ extracted by a biological source

Question 12

What are potential adverse effects of biopharmaceuticals? (2)

Answer 12

-Often result of exaggerated pharmacology or nonspecific anti-drug antibody (ADA)-mediated responses.

-ADAs can neutralise biopharmaceutical activity

Question 13

What do Antibody responses alter to affect the outcome of nonclinical toxicology studies? (4)

Answer 13

1. PK (protein kinase)
2. Tissue distribution
3. Pharmacological activity of biopharmaceutical
4. Interpretation of toxicology data.

Question 14

What is the antibody response to biopharmaceuticals? (4)

Answer 14

-Accelerated clearance of the molecule
-Prolonged exposure
-Neutralise pharmacological activity of biopharmaceutical
-Neutralise the natural, endogenous counterpart protein.

Question 15

What type of molecule is used in immunotoxicology?
When is immunotoxicology used and what is it tested on? (2)

Answer 15

-Small molecule

-Used when toxicity is often unexpected or off-target
-Rodent species is used

Question 16

What does an immunotoxicity study include? (5)

Answer 16

-Haematological changes
-Changes in weight
-Histopathology of immune organs
-Biopharmaceuticals
-Similar approaches taken

Question 17

What are the risks for adverse immune-mediated drug reactions in humans in immunotoxicology? (5)

Answer 17

-Infusion reactions
-Cytokine storm
-Immunosuppression
-Autoimmunity
-Toxicities (need to understand mAb)

Question 18

What are characteristics of immunotherapy? (5)

Answer 18

-May not work at all
-They can eliminate the cancer, or cause it to stabilise, or regress.
-Responses to therapy is longer lasting than those in targeted drugs and tend to persist after patients stop taking the drug
-Immunotherapies work in many cancers and produces cures.
-Only about 20% of cancers tried so far respond to immunotherapy. In pancreatic and most colorectal cancers, it is 0

Question 19

What are the main limitations of CAR-T therapy? (2)

Answer 19

1.T-cells programmed to target CD19 is only common to the surface of a few blood cancers

2.CAR-T has been known to trigger immune reactions that can be fatal

Question 20

What are the potential fatal immune reactions to CAR-T therapy? (4)

Answer 20

• Cytokine-release syndrome (massive release of cytokines in bloodstream)
• B-cell aplasia
• Brain swelling
• Neurotoxicities