Lecture 24 - Biological Therapies for Respiratory Disease

Question 1

Definition of a biological therapy

Answer 1

All pharmaceutically-based therapies that aren’t small molecules (under 1kDa)

Question 2

Nucleotide biological therapies

Answer 2

Anti-sense oligonucleotides such as siRNA, shRNA constructs.

Question 3

Possible uses for nucleotide biological therapies

Answer 3

Therapies for CMV, familial hypercholesterolaemia (ApoB)

Question 4

Current focus of research on nucleotide biological therapies

Answer 4

Focus on packaging and delivery

Question 5

Potential siRNA delivery system

Answer 5

Exosome delivery

Question 6

Recent alternative to monoclonal antibody therapies

Answer 6

Novel protein scaffold technologies.

Proteins that can act like MAbs, but aren’t destroyed in nebulisation process of administration

Question 7

Examples of novel protein scaffold technologies
1)
2)

Answer 7

1) Adnectin - Fibronectin domain bound to IL-23
2) Bivalent diabodies - Bivalent T cell engager (bite) domain binds TCR, tumour cells, leading to cytotoxic killing of tumour cells

Question 8

Example of a disease that is treatable with recombinant proteins
1)
2)
3)

Answer 8

1) Pulmonary alveolar proteinosis.
2) A rare autoimmune disease leading to a deficiency in GM-CSF.
3) Leads to a reduction in neutrophil and macrophage clearance of surfactant in the lungs. Fluid accumulation, impaired gas exchange.

Question 9

How might pulmonary alveolar proteinosis be treated?

Answer 9

Half of PAP patients have autoantibodies against GM-CSF. These patients can be treated with recombinant GM-CSF

Question 10

Advantages and disadvantages of protein scaffolds vs MAbs

Answer 10

Protein scaffolds have a shorter half-life than MAbs, but can be nebulised without being destroyed, therefore can be inhaled.

Question 11

Example of a cell therapy for COPD

Answer 11

Mesenchymal stem cells. These repair tissue, have anti-inflammatory action.
Sources of IL-6, IL-10, TGFb

Question 12

Biomarker for epithelium IL-13 activity

Answer 12

Periostin

Question 13

Role of IL-13
1)
2)
3)

Answer 13

1) B cell isotype switching to IgE
2) Increases number of mucus-secreting cells in airways
3) Activates fibroblasts, increases periostin secretion, which further activates fibroblasts

Question 14

Aim of pharmaceutical treatments of severe asthma

Answer 14

Treatments should either spare the need for steroids, or have a complementary action

Question 15

Monoclonal antibody can binds to IL-13

Answer 15

Lebrikizumab

Question 16

Effect of lebrikizumab

Answer 16

Binds to IL-13, prevents it from binding to IL-13R.

Reduces symptoms of severe asthma in patients with high periostin levels

Question 17

Signalling molecules triggered by IL-13/IL-13R binding

Answer 17

Jak1, Tyk2.

Stat6/stat6 homodimer

Question 18

Way to block both IL-4 and IL-13 action

Answer 18

Block IL-4Ralpha subunit.

This is a subunit of both IL-4R and IL-13R

Question 19

Advantages of cytokine targeting in asthma
1)
2)
3)
4)

Answer 19

1) Selective.
2) Reduces burden of adverse events
3) Shorter development time, more predictable development success.
4) Long half-life

Question 20

Disadvantages of cytokine targeting in asthma
1)
2)
3)

Answer 20

1) High cost of production
2) Must be parenterally administered
3) Many targets are intracellular