Drug Development

Question 1

What are the three main stages of Drug development?

Answer 1

Drug discovery - candidate molecules chosen based on pharmalogical properties

• Preclinical development - non-human studies, toxicity testing, pharmacokinetic analysis and formulaiton
• Clinical development - volunteers and patients, efficacy testing, side-effects and potential dangers

Question 2

What is Avastin?

Answer 2

An antibody - first specific anti-angiogenesis drug

- blocks VEGF

Question 3

What is angiogenesis?

Answer 3

The formation of new blood vessels from pre-existing vessels

• Essential for organ growth in the embryo, and repair in the adult
• Insufficient vessel growth leads to stroke and MI
• Excessive vessel growth leads to cancer and Pulmonary hypertension

Question 4

What are the three types of angiogenesis?

Answer 4

• Developmental/ Vasculogenesis - Organ growth
• Normal angiogenesis - wound repair, placenta during pregnancy
• Pathological angiogenesis - tumour angiogenesis, ocular and inflammatory disorders

Question 5

What is the difference between Angiogenesis and Vasculogenesis?

Answer 5

• Angiogenesis is the development from pre-existing networks, whereas vasculogenesis is where vascular networks develop from progenitors

Question 6

What was the Angiogenesis hypothesis?

Answer 6

That tumour growth is dependent on new vessel growth. If a tumour can be held in a dormant state with no vasculature, metastases may not arise

Question 7

How does Tumour angiogenesis start?

Answer 7

A stimulus such as hypoxia causes the tumour to start secreting angiogenic factors
- The vessel network then allows cells from tumours to spread off and cause metastases.

Question 8

What is VEGF?

Answer 8

• Vascular endothelial growth factor
• Binds to tyrosine kinase receptors on endothelial cells, causing an increase in Ras, PI3 and PLC pathways.
• This causes cell proliferation, expression and survival, leading to angiogenesis

Question 9

Tumour hypoxia

Answer 9

• A strong stimulus for tumour angiogenesis - increases with distance from capillaries
• Activates transcription of genes involved in angiogenesis

Question 10

What is the mechanism of action of Avastin?

Answer 10

• A monoclonal antibody that binds to VEGF, preventing it from activating its receptors on endothelial cells
• This inhibition of VEGF switches off the signal cascade, preventing angiogenesis and so metastases.

Question 11

Steps leading to Avastin development

Answer 11

• Found that there was a mouse antibody that recognised human VEGF
• Major limitation in use of mouse Abs because of the immune response
• Tried to “humanise” the Ab
• Bevacizumab is the resulting anti-VEGF antibody that has similar binding affinity
• Clinical trials
• Approval of use for colorectal carcinoma
• Approval for lung, brain, kidney, ovarian cancers and eye disorders