Lecture 14 - Drug development of novel biopharmaceutical drug Flashcards
What amount of new medicine approvals do biologics account for in the past decade?
1/3rd
What are example of antibody based biologics?
- anti-VEGF
- anti-PD-L1
What are examples of vaccine biologics?
- human papilloma virus (HPV)
- Covid-19
What is an example of RNAi biologics?
- Duchenne Muscular Dystrophy (DMD)
What is an example of cell-based biologic?
CAR-T for children with acute lymphoblastic leukemia
What is an example of gene therapy biologics?
adeno-associated virus (AAV) delivery of Factor IX as a therapy for haemophilia
Describe how animal toxicology in biopharmaceuticals works?
- selection of relevant animal model critical
- surrogate molecule an alternative
- off-target toxicity uncommon
What are the adverse reactions of animal toxicity in biopharmaceuticals?
- exaggerated pharmacology
What are anti-drug antibody (ADA) responses?
- accelerated clearance
- prolonged exposure
- neutralise the pharmacological activity
What is the max dose?
10x maximum exposure in clinic
What is the surrogate model assessment?
another drug developed which mimics role of first drug in animals
What is immunotoxicology in a small molecule?
unexpected and off-target
How does immunotoxicology relate to biopharmaceuticals?
- through understanding required to anticipate risk
- infusion reaction
- cytokine storm (NHP blood cell cytokine release assays)
Ph1 dose: minimum anticipated biological effect
What questions are asked in Phase 1?
- Is it safe?
- How well is it tolerated?
- What are the pharmacokinetic properties?
- Is it ethical or possible to test healthy volunteers?
What occurred with the TGN1412 incident?
- Stimulant on T-cells
- CB28-SuperMAB
- Preclinical profile - very good
- Dose - 500 lower
- 6 volunteers in hospital
- cytokine release syndrome
What is immunotherapy?
a form of cancer treatment that uses the immune system to attack cancer cells, in much the same way that attacks bacteria or viruses.
What are checkpoint inhibitors?
Releasing a natural brake on your immune system so that immune cells called T cells recognise and attack tumours
What is CAR-T cell therapy?
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.
Describe the immunotherapy timeline
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
What occurs when drugs inhibit PD-L1?
Releases the ‘brake’ on the immune system, allowing for tumour cells to be attacked by T-cells
Describe the production of Pembrolizumab (Keytruda)
- 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)
What characteristics to Pembrolizumab (Keytruda)?
- 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
What are the stages of CAR-T (chimeric antigen receptor-T cell Therapy)?
1) T cell collection
2) T cell transfection
3) T cell adoptive transfer
4) Patient Monitoring
What occurs during T-cell collection?
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).
What occurs during T-cell transfection?
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.
What occurs during T cell adoptive transfer?
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.
What occurs in patient monitoring?
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.
What are the limitations of Chimeric antigen receptor T-cell therapy (CAR-T)?
- CD19, which is only common to the surface of a few blood cancers
- immune reactions which can prove fatal
Describe features of CAR-T Therapy (Kymriah)?
Extremely effective
- trial: acute lymphoblastic leukemia
- 29/31 patients unprecedented remission (cancer gone)
What are the limitations of CAR-T therapy (Kymriah)?
- Target molecule (CD19) only on few blood cancers
Fatal immune reactions:
- cytokine-release syndrome
- B-cell aplasia
- Brain swelling
- Neurotoxicites
