Flashcards in Lecture 25 - Biological Therapy for Respiratory Diseases Deck (22):
Define biological therapy
List a few examples
• Living organisms
• Living organism-derived products
• Lab produced versions
• Immunotherapy: vaccines, bacteria
Describe the use of nucleotide sequences in biological therapy
Used as: Antisense oligonucleotides
• Marketed for CMV and ApoB
What are exosomes?
Vesicles released by a cell via exocytosis
How can exosomes be used therapeutically?
Exosomes can be engineered to contain desired components for delivery to cells:
• Introduction of nucleic acids via Exoporesis
• Small molecule loading
Particularly useful in administration of highly charged molecules that normally cannot cross plasma membranes
Outline the generation of mAbs
1. Spleen cells from antigen challenged mice + myeloma cells
2. Membranes forced to fuse with PEG
3. HAT kills off myeloma cells that did not fuse
4. Spleen cells are now immortal hybridomas
5. Screening to look for the mAb specificity of interest
When was the generation of mAbs discovered?
Who designed this process?
Milstein & Köhler, 1975
When were mAbs first humanised?
When were human mAbs first produced?
Describe how they were produced
2002 - Adalimumab (anti-TNF)
Generated from spleen cells of transgenic mice (have complete human Ig genes)
Describe therapeutic use of novel protein scaffold technology
What are recombinant proteins?
Give an example of therapeutic use of R.P.s
• Proteins derived from recombinant DNA
• DNA formed by laboratory methods of genetic recombination (such as molecular cloning) to bring together genetic material from multiple sources
• Creates sequences that would not otherwise be found in biological organisms
• Recombinant GM-CSF in PAP (pulmonary alveolar proteinosis)
What is pulmonary alveolar proteinosis (PAP)?
Describe the mechanism, pathology, symptoms and murine model
Accumulation of surfactant in the alveoli
• Loss of GM-CSF activity
• Reduced macrophage and PMN clearance of surfactant in the alveoli
• Alveolar oedema
• Impaired gas exchange
• Dyspnoea and cough
GM-CSF -/- mice:
• Exhibit PAP like disease
Observation in PAP individuals:
• Anti-GMCSF autoantibodies
• Can PAP in mice with infusion of these Abs
How has PAP been treated in the past?
How could it be treated now?
• Lung lavage
• Administration of recombinant GM-CSF
Outline cell therapy for respiratory disease
Mesenchymal stem cells
• Tissue repair
• Anti-inflammatory effects
Outline vaccine / adjuvant therapy for respiratory disease
What is the rationale?
Give examples and challenges
Vaccination against viruses that exacerbate COPD and asthma
• Influenza vaccine
NB There are many serotypes for these viruses, so vaccination is challenging
Describe cytokine targeting of respiratory disease
e.g. In severe asthma
• Not controlled by LABA/ICS
• anti-IL-13 mAb
• Prevents IL-13 from binding to receptor subunit IL-4Rα
IL-13 role in asthma:
• IgE class switching
• Macrophage stimulation
• Smooth muscle stimulation
• Differentiation of respiratory epithelium into goblet cells
• Activation of fibroblasts
Describe how Lebrikizumab was trialled
Serum periostin is a marker of IL-13 activity:
• When IL-13 acts on respiratory epithelium, periostin is release and detectable in the serum
• Individuals with high or low periostin
• Control + Lebrikizumab groups
Primary outcome measure:
• Change in FEV1
• Asthma control not complete, but probably improved
• Primary outcome was met (there was improvement in FEV1 in treatment group)
Describe the IL-13 receptor
What is Dupilumab?
Dupilumab: anti-IL4Rα mAb
What are the benefits of Dupilumab over Lebrikizumab?
Lebrikizumab prevent IL-13 from binding IL-4Rα subunit of the IL-13R, but also prevented IL-4 binding to IL-4Rα of IL-4R
Describe trials of Dupilumab
• Individuals with asthma
• Two groups: treatment + placebo groups
Primary outcome measure:
• Frequency of exacerbations
• FEV1 increase
• Increased FEV1 on Dupilumab
• 87% reduction in exacerbations on drug
What are the advantages and disadvantages of cytokine targeting therapy over ICS for the treatment of asthma?
• Selective: decreased burden of adverse effects
• Long half life
• Expensive production costs
• Parenteral administration
• Many targets are intracellular