Advances in Monoclonal Antibody Therapy Flashcards
Small molecule drug
- Low MW
- Chemically synthesised (defined chemical reactions)
- Simple, well defined structure
What are small molecules known as?
The pillars of traditional medicine
Examples of small molecule drugs targets
Extracellular proteins
Intracellular receptors
In cytoplasm, nuclei, CNS
Examples of small molecule drugs
Aspirin
Penicillin
Paracetamol
Lipitor (Atorvastatin)
Biological molecule
- High MW
- Derived from living organisms (manufactured)
- Large, complex, dynamic structure
Uses of large biologics
- Therapeutic proteins (peptides, antibodies)
- Nucleic acid based therapies (RNAi, gene therapy/editing)
- Blood components
- Cellular therapies (e.g. CAR T-cell therapy)
- Tissue therapies (allogenic transplants)
50% of biologics marketed today are?
Monoclonal antibodies (fastest growing class of drugs)
Monoclonal antibody
An example of a biologic
High specificity, allowing the stimulating of the immune system to attack certain antigenic cells
What is the large biologic that is the 2nd best selling drug (2021)? What is it used for?
Humira (mAb)
- Autoimmune disease treatment (rheumatoid arthritis, psoriatic arthritis, Crohn’s, psoriasis)
- Forecasted to be replaced by Keytruda by 2024 (mAb for cancer immunotherapy)
Small molecules vs Biologics
Small mol: low MW, simple structure, independent of manufacturing process, identical copies possible, well-defined, stable, non-immunogenic
Biologic: high MW, complex structure, defined by exact manufacturing process, identical copies impossible, can’t be characterised completely, unstable, immunogenic
Advances in biotechnology enabled?
Synthesis of biological molecules (proteins) in microorganisms & other living cells (via recombinant DNA technology)
Key areas for mAb use
- Immunotherapy
- Inflammatory diseases
- Autoimmune diseases
- CVD
- Oncology
- Neurodegenerative diseases
- COVID-19
Briefly discuss mAb therapy
- Very specific
- Immunotherapy
- Uses mAbs to bind monospecifically to certain cells or proteins
- Stimulation of patient’s immune system to attack certain cells
Antibody functions
- Neutralisation
- Agglutination
- Precipitation
- Complement activation
How do mAbs work?
- Variable region of antibody binds to a single antigen
- Specific binding
- mAbs are useful for highly targeted therapeutic administration
- Minimises adverse off target side effects
- Useful for delivery of toxic drugs
True or False: The host’s immune system produces long-term Abs after short-term mAb drug administration
True
The first reliable source of mAbs
Immunotherapy, 1970s, Hybridoma technology
- Orthoclone 1986 - limited organ transplant rejection
- Can take the hybridoma out of the mouse & modify it → develop it into a mAb
The biggest manufacturing problem associated with mAbs
Low stability
Discuss Keytruda (Pembrolizumab)
Humanised mAb used in cancer immunotherapy
- Binds specifically to PD1
- Few severe adverse events (5%: fatigue, rash, dry mouth)
- Can be combined with targeted and untargeted drugs
(i) Chemotherapy
(ii) Radiotherapy
(iii) Immune modulators
What is PD-1?
PD1 = programmed cell death protein 1
- PDL-1: transmembrane protein of cancer cells, which prevents PD-1 from identifying it & the immune system from killing the cancer cells
PD1 blockade: ↑ T-cell mediated anti-tumour immunity, inhibits T-cell PD1/tumour cell PD1 interaction, potential treatment strategy
Is cytotoxic activity associated with Keytruda?
Cytotoxic activity occurs when Fc receptors are engaged and the complement system is activated. This does not occur in Keytruda → no cytotoxic activity
Keytruda and metastatic melanoma
median survival <12 months
- Assoc. with genetic mutations
- Inhibitors - 10% response
- Conventional chemotherapy ineffective
- Few treatment options
- Keytruda - for non-responders/relapse
- 1st trial saw up to 52% overall response rate
- Overall response rates consistently higher than chemotherapy
- Progression free survival higher than chemo
- Improved safety profile vs chemo & other mABs (ipilimumab)
- FDA approved 2014
Keytruda and non-small cell lung cancer (NSCLC)
- NSCLS: median survival ~10 months
- Platinum based chemotherapy (first line treatment)
- Few other options
- 1st PD1 blockade trial: Nivolumab
- ↑ overall response rate to 20% compared to 9% seen with chemo
- Keytruda - overall survival superior to chemotherapy
- ↑ when >50% of tumour cells expressed PDL1
- ↑ progression free survival
- Fewer adverse events
- FDA approved 2015
Keytruda and lymphoma
↑ PDL1 expression in Hodgkin Lymphoma
- Good response to PD1 blockade
- Nivolumab - 87% overall response rate
- Keytruda for non-responders/relapse/ineligible for transplant
- Poor response in early studies/trials
- Toxicity (dosages v important) & SAEs
- 2mg/kg every 3 weeks - complete response, no toxicity
- Lower doses could be more useful for lymphoma treatment
