Lecture 14 - Drug development of novel biopharmaceutical drug

Question 1

What amount of new medicine approvals do biologics account for in the past decade?

Answer 1

1/3rd

Question 2

What are example of antibody based biologics?

Answer 2

• anti-VEGF
• anti-PD-L1

Question 3

What are examples of vaccine biologics?

Answer 3

• human papilloma virus (HPV)
• Covid-19

Question 4

What is an example of RNAi biologics?

Answer 4

• Duchenne Muscular Dystrophy (DMD)

Question 5

What is an example of cell-based biologic?

Answer 5

CAR-T for children with acute lymphoblastic leukemia

Question 6

What is an example of gene therapy biologics?

Answer 6

adeno-associated virus (AAV) delivery of Factor IX as a therapy for haemophilia

Question 7

Describe how animal toxicology in biopharmaceuticals works?

Answer 7

• selection of relevant animal model critical
• surrogate molecule an alternative
• off-target toxicity uncommon

Question 8

What are the adverse reactions of animal toxicity in biopharmaceuticals?

Answer 8

• exaggerated pharmacology

Question 9

What are anti-drug antibody (ADA) responses?

Answer 9

• accelerated clearance
• prolonged exposure
• neutralise the pharmacological activity

Question 10

What is the max dose?

Answer 10

10x maximum exposure in clinic

Question 11

What is the surrogate model assessment?

Answer 11

another drug developed which mimics role of first drug in animals

Question 12

What is immunotoxicology in a small molecule?

Answer 12

unexpected and off-target

Question 13

How does immunotoxicology relate to biopharmaceuticals?

Answer 13

• through understanding required to anticipate risk
• infusion reaction
• cytokine storm (NHP blood cell cytokine release assays)

Ph1 dose: minimum anticipated biological effect

Question 14

What questions are asked in Phase 1?

Answer 14

• Is it safe?
• How well is it tolerated?
• What are the pharmacokinetic properties?
• Is it ethical or possible to test healthy volunteers?

Question 15

What occurred with the TGN1412 incident?

Answer 15

• Stimulant on T-cells
• CB28-SuperMAB
• Preclinical profile - very good
• Dose - 500 lower
• 6 volunteers in hospital
• cytokine release syndrome

Question 16

What is immunotherapy?

Answer 16

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

Question 17

What are checkpoint inhibitors?

Answer 17

Releasing a natural brake on your immune system so that immune cells called T cells recognise and attack tumours

Question 18

What is CAR-T cell therapy?

Answer 18

Chimeric antigen receptor (CAR) T cell therapy is an approach in which scientists genetically engineer a patient’s own immune cells to make a new protein. This turns them into supercharged cancer fighters.

Question 19

Describe the immunotherapy timeline

Answer 19

1976 - Interleukin 2 (many serious adverse effects)

1990 - Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on T-cell surface 0 when blocked –> tumours vanished

1999 - Programmed Cell Death Protein 1 (PCD1) tamps down immune system. Programmed death-ligand 1 (PD-L1) protects cancer from T-cell

Question 20

What occurs when drugs inhibit PD-L1?

Answer 20

Releases the ‘brake’ on the immune system, allowing for tumour cells to be attacked by T-cells

Question 21

Describe the production of Pembrolizumab (Keytruda)

Answer 21

• 2006 invented at Organon
• 2007 Shering-Plough acquired Organon
• 2009 acquired by Merck with little interest
• 2011 Phase 1 trial (breakthrough therapy designation - 1300 patients)

Question 22

What characteristics to Pembrolizumab (Keytruda)?

Answer 22

• may not work at all
• can eliminate cancer, stabilize or regress
• long lasting
• difference in response
• Hodgkins lymphoma - 90%
• Pancreatic, colorectal cancer - 0%
• Research landscape shifted - 1000+ clinical trials

Question 23

What are the stages of CAR-T (chimeric antigen receptor-T cell Therapy)?

Answer 23

1) T cell collection
2) T cell transfection
3) T cell adoptive transfer
4) Patient Monitoring

Question 24

What occurs during T-cell collection?

Answer 24

This is the first step where T-cells (a type of immune cell) are taken from the patient’s blood. The process is called apheresis, where blood is drawn from the patient, and T-cells are isolated and separated from the rest of the blood components (like red blood cells and plasma).

Question 25

What occurs during T-cell transfection?

Answer 25

In this step, the collected T-cells are genetically modified in the laboratory. Scientists add a new Chimeric Antigen Receptor (CAR) to the T-cells. The CAR is a special receptor that allows the T-cells to recognize and attack specific cancer cells.

Question 26

What occurs during T cell adoptive transfer?

Answer 26

After the T-cells are modified with the CAR, they are multiplied (expanded) in the lab to create a large number of these modified T-cells. Once there are enough, they are infused back into the patient.

Question 27

What occurs in patient monitoring?

Answer 27

After the CAR-T cells are infused into the patient, they are closely monitored to check how they are working and how the patient is responding to the treatment. This involves regular tests, such as blood work, to look for side effects or complications like cytokine release syndrome (CRS) or neurological issues.

Question 28

What are the limitations of Chimeric antigen receptor T-cell therapy (CAR-T)?

Answer 28

• CD19, which is only common to the surface of a few blood cancers
• immune reactions which can prove fatal

Question 29

Describe features of CAR-T Therapy (Kymriah)?

Answer 29

Extremely effective
- trial: acute lymphoblastic leukemia
- 29/31 patients unprecedented remission (cancer gone)

Question 30

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

Answer 30

• Target molecule (CD19) only on few blood cancers

Fatal immune reactions:
- cytokine-release syndrome
- B-cell aplasia
- Brain swelling
- Neurotoxicites