Flashcards in Lecture 24 - Biological Therapies for Respiratory Disease Deck (20):
Definition of a biological therapy
All pharmaceutically-based therapies that aren't small molecules (under 1kDa)
Nucleotide biological therapies
Anti-sense oligonucleotides such as siRNA, shRNA constructs.
Possible uses for nucleotide biological therapies
Therapies for CMV, familial hypercholesterolaemia (ApoB)
Current focus of research on nucleotide biological therapies
Focus on packaging and delivery
Potential siRNA delivery system
Recent alternative to monoclonal antibody therapies
Novel protein scaffold technologies.
Proteins that can act like MAbs, but aren't destroyed in nebulisation process of administration
Examples of novel protein scaffold technologies
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
Example of a disease that is treatable with recombinant proteins
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.
How might pulmonary alveolar proteinosis be treated?
Half of PAP patients have autoantibodies against GM-CSF. These patients can be treated with recombinant GM-CSF
Advantages and disadvantages of protein scaffolds vs MAbs
Protein scaffolds have a shorter half-life than MAbs, but can be nebulised without being destroyed, therefore can be inhaled.
Example of a cell therapy for COPD
Mesenchymal stem cells. These repair tissue, have anti-inflammatory action.
Sources of IL-6, IL-10, TGFb
Biomarker for epithelium IL-13 activity
Role of IL-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
Aim of pharmaceutical treatments of severe asthma
Treatments should either spare the need for steroids, or have a complementary action
Monoclonal antibody can binds to IL-13
Effect of lebrikizumab
Binds to IL-13, prevents it from binding to IL-13R.
Reduces symptoms of severe asthma in patients with high periostin levels
Signalling molecules triggered by IL-13/IL-13R binding
Way to block both IL-4 and IL-13 action
Block IL-4Ralpha subunit.
This is a subunit of both IL-4R and IL-13R
Advantages of cytokine targeting in asthma
2) Reduces burden of adverse events
3) Shorter development time, more predictable development success.
4) Long half-life