Biologics

Question 1

What are the types of biological drugs?

Answer 1

• Monoclonal antibodies (mAbs)

•	Proteins/peptides
o	Cytokines
o	Growth factors
o	Enzymes
o	Immunomodulators

• Nucleotide-based therapeutics
o microRNA inhibitors/mimics

Question 2

What is the difference between small molecules and antibodies and give examples?

Answer 2

Small Molecules

• Small size generally means they can be designed with properties to easily enter cells
• Can target intracellular molecules
• Lapatinib
• Binds to intracellular phosphorylation domain of the receptor

Antibodies
• Larger molecules cannot penetrate cells
• Generally restricted to targeting receptors or ligands

• Trastuzumab
• Binds to HER2 receptor on cell membrane

Lapatinib – can penetrate the cell therefore can target the phosphorylation domain receptor and modulate receptor activity and intraceullar pathway downstream of that receptor. Affects ability of cells to grow

Antibody approach – have to target outside the cell so antibody binds to receptor and that blocks binding of the EGF ligand to the receptor and affects downstream signalling. Therefore, blocking cell growth.

Drugs are the same but act differently

Question 3

What is a Bi-specific antibody?

Answer 3

• Designed when you want to target 2 different proteins
• Or for two sites on same protein (bi-paratopic)

Bi-specific – an antibody that made by joining two halves of an antibody. Each antibody targets a protein (therefore 2).

Can hit one target but in two different places (bi-paratopic).

Question 4

What route of administration are biologics given?

Answer 4

Biologics are most often given intravenously, sub-cut or intra-muscular injection
• Oral bioavailability is poor due to enzymatic digestion in GI tract

Question 5

How do you get immunogenicity to biologics?

Answer 5

Immunogenicity
• Production of anti-antibody antibodies (ADA)
»Potential adverse events
• Production of neutralising antibodies (NAb)

> > Decrease in efficacy over time and potential treatment failure

Question 6

What is the Drug-Drug Interaction (DDI) between Tocilzumab and Simvastatin?

Answer 6

• Patients with rheumatoid arthritis, Sjrogrens, have elevated pro-inflammatory cytokines
• Has the effect of reducing Cytochrome (CYP) activity – CYP reduces drug metabolism in the liver
• Thus reduces drug metabolism in liver and increases exposure time of Simvastatin

Lower levels of metabolism in RA, Sjrogens, therefore higher exposure.

Question 7

Information

Answer 7

Infliximab is a chimeric antibody (mixture of mouse and human – variable domain is from the mouse and Fc is human - binding to human reduces immunogeneicty).
• Variable domains from mouse
o Combined with constant domains from human to reduce immunogenicity

Question 8

What is Lead optimisation ?

Answer 8

a lead molecule which will be developed into the drug