Lecture 10 - Drug discovery and development 2 Flashcards
complexity of small molecules
- low molecular weight
- chemically synthesised
- well defined structure
complexity of biological molecules
- high molecular weight
- derived from living organisms
- large and complex structure
complexity of monoclonal antibodies
- high molecular weight
- derived from living organisms
- more complex structure
what are biopharmaceuticals?
- defined as products where the active substance is produced/ extracted by a biological source
what was the first biopharmaceutical produced?
insulin approved by FDA in 1982
what are biopharmaceuticals made of?
includes recombinant and monoclonal antibody-based products and recombinant vaccines.
biopharmaceutical model
- highly specific for a human target and most used is NHP (e.g. macaque monkey) where it will be used for the whole nonclinical safety program.
what is a surrogate molecule?
proteins that recognise the target in an animal model that is analogous to the human target recognised by the clinical products. Allows hazard detection for pharmacological activity
Cause of adverse reactions for biopharmaceuticals?
result of exaggerated pharmacology or nonspecific anti-drug antibody (ADA) mediated responses.
role of immunogenicity
distinguishes biopharmaceuticals from small-molecule drugs and is a cofounding factor when testing human proteins in animal models
what is the effect of ADA’s on biopharmaceuticals?
neutralise their activity, reduce exposure and elicit ADA-mediated toxicities in the animal model
what would cause an immune response for biopharmaceuticals?
greater dissimilarity between the human protein sequence and animal protein sequence
how does antibody responses affect the outcome of nonclinical toxicology studies?
alters the pK, tissue distribution, pharmacological activity of biopharmaceutical and interpretation of toxicology data
why is it important to measure presence of ADA’s?
determines potential correlation with pharmacology, PD, PK, or immune mediated toxicity
when are ADA measurement studies conducted?
if there is an altered PD activity, changes in exposure in absence of PD or immune-mediated toxicity
what are the antibody responses to biopharmaceuticals?
- accelerated clearance of molecule
prolonged exposure
neutralise pharmacological activity
neutralise the natural, endogenous counterpart protein.
what is the maximum dose for the nonclinical animal model?
dose is 10x the maximum exposure in the clinic
what does an immunotoxicity study include for small molecules?
- haematological changes
- changes in weight
- histopathology of immune organs
what is the inherent risk for adverse immune-mediated drug reactions in humans?
- infusion reactions
- cytokine storm
- immunosuppression
- autoimmunity
how to test the clinical risk of adverse immunotoxicological events
select a safe starting dose with immunomodulatory mAbs based on the minimum anticipated biological effect level and its selection of a safe maximum recommended starting dose
cause of toxicities arising from use of pharmacologic immunostimulation
caused by imbalances in cytokine signalling
what happens in phase 1 of clinical testing for biopharmaceuticals?
aim is to test if drug is safe to humans and performed on small group of normal healthy volunteers (20-80). tests for pharmacodynamic effects in volunteers
what does phase 1 clinical testing check signs for?
- dangerous effects on organ systems
- tolerability
- pharmacokinetic properties
what is immunotherapy?
form of cancer treatment that uses immune system to attack cancer cells in the same way it would for an immune response against pathogens
