Biological therapies Flashcards
(38 cards)
Why talk about cancer
• Biggest investment (most money spent in healthcare)
• Carries the biggest emotional burden
• Kills people
• Has a lot of unmet needs
• Fastest progression in oncology
- In terms of therapeutic area (biggest expanding)
• Need for new cancer therapies
Definition of biological therapies
A biological medicine is a medicine that is derived from a biological (living) source, such as bacteria or viruses, blood, tissues or living cells in culture’ (MHRA 2017)
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Biologic vs small molecule
Biologic is produced by a living organism - Whereas small molecules are chemical entities • Examples of biologics include: - Monoclonal antibody (mAb) - Gene therapy - RNA therapeutics - Somatic cell therapy - Blood coagulation factors - Vaccines - Peptides (e.g. insulin) • Small molecules move intracellularly - Small molecules are significantly smaller than biologics
Anti-cancer treatment
- Surgery
– Early stage, low risk patients (patients less likely to die)
– Surgery doesn’t benefit people with curative intent
– Whereas the other treatments are done for curative intent + prolonging therapy - Radiotherapy
– Ionising radiation – X ray, γ-ray, neutrons, electron and protons
– External/Internal - Systemic therapy
– Cytotoxic chemotherapy
– Hormonal therapy – Breast/prostate
– Targeted therapy
– Immunotherapy
• Systemic therapy used to small molecules (chemotherapy)
– This is the backbone of cancer, but now there are different types of therapy
• Anti-cancer treatment has made tremendous progression in the last 20yrs
traditional chemotherapy
• Maximum tolerated dose
- Single ascending dose
- You want to give the highest dose to kill the cancer cells (but you can also kill healthy cells that are actively dividing)
- so you need a dose that won’t cause too much harm & kill normal cells
- maximum tolerated dose is very important (do not want cytotoxicity)
- Treatment cycles seen a lot in chemotherapy
• Administered as treatment cycles (e.g. 3 weeks)
– Balance recovery time of normal tissues, amount of cancer cell death and adverse reactions
– Patients need time to recover (allowing healthy cells to recover but achieve maximum kill of cancerous cells)
• Chemotherapy regimens often consist of multiple agents need multiple treatments)
– working synergistically targeting different phases of the cell cycle to↑ cell death
– e.g. alkylating agents work around different phases of cell cycle, but toxoids only work on G2 & M phase (they work on different phases of cell cycle to get max kill)
• ↓ therapeutic resistance and toxicities (normal dividing cells)
- Cancer cells can become resistant due to mutations
- The same patients have very different genetic makeups & cancers create their own microenvironments
- Chemotherapy agents work on different parts of the cell (can lead to toxicities)
– Multiple treatments can lead to toxicities such as:
• Gastrointestinal tract – N&V
• Bone marrow - myelosuppression
• Peripheral neuropathy
• Systemic: fatigue and anorexia
Note: response rate is variable, approximately 15-20% for a single agent
- Using single agent = lower response rate (big unmet need)
Targeted therapy in cancer
Definition: same systemic treatment targeting specific molecular pathways, such as:
• Cell proliferation
• Protein synthesis
• Angiogenesis (growth & formation of new blood vessels)
• Immune cells regulations
Companion diagnostics:
• Driver mutations within the somatic genome that enhance cancer cell growth in cancer cells
• Companion diagnostics – identify oncogenes that drugs can target
- Need to identify the driver mutation via a test to identify the main oncogene involved - so drugs can target oncogene
- Targeted therapy (need companion diagnostics for it)
- Not only do you design a drug but you design a good pathway that is identified for further research (increases complexity in drug development process)
Schemes for targeted therapy
• Trastuzumab/Pertuzumab = most successful oncology drug in the last 20yrs
- They target HER2 receptor
• Hormones = old school targeted therapy
- Intracellular receptors (Usually small molecules)
• Growth factor receptors & tumour microenvironments = biologics
- Biologics target extracellularly need soluble receptor that exists around the blood / on cell surface)
- too big for intracellular targeting ( cannot cross the cell membrane )
• Monoclonal biologics are more specific
• You would get less off target effects with biologics
- Off target pharmacology = 2nd pharmacology / pharmalogical effects that you would not expect)
Toxicity is drug dependent – targeted therapy does not reduce chance and severity of potential toxicities
Immunotherapy
• Type of targeted therapy
• Tumour infiltrating lymphocytes (usually T cells – physiologically identify & kill cancer cells)
– Identify and destroys abnormal/cancer cells
– Natural Immune system response to cancer
– Cancer cells have multiple mechanism evading immune response e.g.
– Mutations – evasion of cancer cells identification (can’t be identified)
– Cell surface protein inactivating T-cells
– Alteration in tumour microenvironment to prevent interactions with immune cells
• Tumour heterogeneity – genetic and phenotypical variations between cancers cells of the same patient treatment response ↓
- Difficult to treat cancer with curative intent (hard to completely eradicate cancer cells)
• Immunotherapy activates systemic tumour-specific CD8+ cytotoxic T lymphocyte (CTL) responses against cancer cells
– Overcoming immune evasion
– Bypass tumour heterogeneity
In tumour heterogeneity – once the immune system is activated = you make it more active
- Achieve higher cancer kill
Why is there a problem with making immune system more immunogenic (more activated)?
- = increased risk of autoimmune disease
- Autoimmunity is a big problem in immunotherapy
• 3 types of immunotherapies:
- Antibody-based ‘checkpoint’ inhibition
- Adoptive T cell therapy
- Therapeutic vaccination (least advanced – in terms of bringing it into clinical practice
comparison of biologics and small molecules
• Biologics can only hit surface receptor (extracellularly)
• Small molecules can hit surface receptor & intracellular pathways at different time points
• Bispecific antibody – can target 2 things specifically, not just 1 like other antibodies
• Antibody drug conjugate (ADC) – new technology
- Antibody is loaded with cytotoxic drug & upon binding with the right receptor
- = cytotoxic drug gets released & undergoes it’s mechanism of action
• Gene therapy = still under development
- The ASO (antisense oligonucleotide) (small pieces of DNA or RNA which can bind to specific molecules of RNA and block the ability of RNA to make a protein) / RNA therapeutics are getting more common
- They need to be inside the cell with the RNA (intracellular)
• Newer developments will mean that biologics might be able to target intracellularly
Monoclonal antibodies
• Fab (fragment antigen binding portion) is where the antigen is
- Monoclonal = so recognises 1 antigen
• Most mAb are IgG
• Need to be injected (problem delivering to patients)
- Too big to pass through if swallowed
- Novel mAbs can be swallowed but only works topically in the guts & it can get into the system
Monoclonal (mAb) advantages
• Most mAbs are mostly IgG
- It follows IgG does in the body & the Pk of that mAb antibody
- It’s a starting point for mAb & then it can be modified
• Advantages
– Single target antigen specific, limited or no off-target effects
• Toxicity relates to on-target, off tumour toxicities
- If you have immunotherapy; you get immune system that targets cancer but immune system also targets other parts of the body (on target – off target tumour toxicities)
• Drug interactions: mostly pharmacodynamic
– Long acting (because its monoclonal
Monoclonal (mAb) disadvantages
– Require cell surface or soluble receptor targets
– Parenteral – oral administration has limited systemic applicability
– Long acting (If you have a problem – you need to wait for the drug to clear)
– Immunogenicity
- If you inject antibody into the system, the immune system will react to the monoclonal making it unpredictable in terms of PK
- Immunogenicity can also cause immune reactions
- For biologics immunogenicity is the biggest problem
- For small molecules immunogenicity is not a problem
what is immune CHECKPOINT`
• Immune checkpoint molecules are expressed on cell surface of the adaptive immune system, particularly on T cells, and of the innate immune system
• They are crucial for maintaining the self-tolerance (prevent autoimmunity) and modulating the duration and magnitude of immune responses of effectors in different tissues to minimise the tissue damage
- Crucial to avoid auto-immune reactions
checkpoint inhibitors - mAB
• Checkpoint inhibitors = allow tumour cells to get immune response
- Inactivation of the checkpoint
- Tumour cells kill by deactivating the immune system (inhibition of PD1 – with PDL1)
- Therefore, T-cells are not activated to kill tumour cells
• Checkpoint inhibition via mAbs allow reactivation of T helper cells reactivation
• Checkpoint inhibitors is a game changing drug that has become standard of car for lung cancer
• However, Immune related adverse reactions
Monoclonal antibodies vs chemical drugs:
weight:
production:
Antibody drug conjugate (ADC)
- ADCs are most effective when the target cell surface antigens are highly expressed in tumour cells but not in healthy tissues
- The cytotoxic ‘payload’, which is the ultimate effector part of the ADC, is highly potent and characterised
- The linker to the payload is crucial to the therapeutic window - stability vs ease of release
- Systemic toxicity is related to small molecule payload
• Payload / warhead = once it binds to cell surface, it gets released
• Most important component of ADC is the linker
• You need to have a good understanding of the cytotoxic drug that you want to use as a payload
- as it needs it will a very specific cellular target & need a very small dose
• you use a small dose to target the cell you want = larger effect with smaller dose & less likely to get systemic toxicity
- This is why people are interested in ADC
• However in reality it doesn’t work like that !!!
- If the linker is attached too tight to payload = cytotoxic drug is not released & does not kill cancerous cells
- If the linker is attached too weakly to payload = cytotoxic drug is released everywhere = increased toxicity (+ you get chemotherapy as well)
- ADC has to deal with toxicity
• ADC linker technology is very important for ADCs to work effectively
ADC mechanism of action
• ADC work by:
- Binding to antigen
- Undergo ADC receptor mediated internalisation via endocytosis
- Apoptosis of drug target cell
- Degradation of ADC in lysosomes
- Payload release of cytosol
• All of these lead to cytotoxic mechanism = leads to fall of cancerous cell cycle
ADC - Ado-trastuzumab emtansine
• ADC that conjugates trastuzumab to the microtubule inhibitor DM1 (one of the most successful ADC)
– Trastuzumab is a mAb binding the human epidermal growth factor receptor 2 (HER2) standard of care in HER2 breast cancer (15-20%) for 20 years
– Trastuzumab silenced intracellular signalling and stimulated immune responses, but resistance is common
– DM1 is added as a cytotoxic payload
• Trastuzumab is already very successful in breast cancer – adding cytotoxic payload – increase efficacy
• However, cytotoxicity is a issue because of linker technology
Bispecific antibodies
• Bispecific antibodies are capable of binding two target antigens
– Simultaneously modulate two signalling pathways in the same disease target (e.g. dilpacimab, an antiangiogenic agent targeting both the delta-like ligand four and vascular endothelial growth factor pathwaysss DIAGRAM B)
– Encourage the binding of both cells and proteins (bridging cells) e.g. blinatumomab promoting binding of T cells to tumour cells in oncology
– Blinatumomab = most advanced (used in myeloid leukaemia & haemophilia)
– Monoclonal are only specific to 1 antigen
• Bispecific antibodies have a variable construct:
– Ranging from a whole IgG-like molecule to a smaller molecule with just a single-chain variable fraction. The PK is dependent on size and therefore more variable than mAb
– Used 40/50 constructs = variety in co-receptor to conceptualise the mechanism (but vey useful)
• Only cell surface or soluble target
• Diagram:
- A = bispecific antibodies bridge the cell
- You can get cancer cell & bridge it to an effector cell (e.g. immune cells)
- B = activate 2 pathways they might not be activated at the same time point but you bind them together
- Activation leads to down streaming events = receptor inhibition
• Useful tool as you can simultaneously block two useful pathways
Adoptive T-cell therapy
• A ‘living’ drug – T-cell based immunotherapy (actual living cells e.g. T-cell transfusion)
1: Tumour-Infiltrating Lymphocyte (TIL) Therapy
• Selection of pre-existing TIL in patients
- Concentrate the T-cells and give them to the patient (it’s what they naturally produce in their body)
- Identify what can kill cancer & grow it and give it back to the patient
2: Engineered T Cell Receptor (TCR) Therapy
• Engineered T-cell receptor insertion to bind to tumour antigen presentation via MHC
- Overcome T cells with a lack of receptor to identify the cancer
- The T cells don’t identify the receptor naturally ( so you insert T-cell receptor you want to identify) & give it back to the patient
3: Chimeric Antigen Receptor (CAR) T Cell Therapy
• Chimeric antigen receptor insertion to bind to tumour even without antigen presentation via MHC
- Create an antigen receptor insertion
- Creates an extra receptor without relying on antigen presentation via MHC cells
- You can activate T cells independent of MHC antigen presentation
• Adverse events: cytokine release syndrome (CRS)
- CAR T-cell therapy is a very powerful form of immunotherapy & can read to CRs (massive inflammatory reaction)
Problems with T-cell therapy
• The problem with these therapies is the duration of response
- They don’t work forever (develop resistance)
- They are still experimental (need to get good quality results consistently)
• Lymphodepletion chemotherapy has been used recently
- Very powerful if it works but some cells may not respond
- Red dot = stage where you can lymphodepletion chemotherapy before give the Adoptive T-cell therapies back to the patients
- It has been used to decrease myeloid suppressor cells (cells that can suppress immune system) & T cells
- So, the T-cells that you induce get a lot of immunotherapies
- However, drawback = increased cytokine release syndrome (CRS)
CAR-T cell therapy
Engineered CAR-T cell receptor, which is independent of antigen presentation
- Therefore a lot more flexible
• However, very individualised for every cancer cell
- Need new receptor needs to be produced every time
• CAR-T receptor many not always bind as cancer cells can be very heterogenous in terms of receptor presentation
- They can have mutations
RNA therapeutics
• ASO = antisense oligonucleotides =
Small pieces of DNA or RNA that can bind to specific molecules of RNA. This blocks the ability of the RNA to make a protein or work in other ways.
• RNA therapeutics used to silence gene / mutation
• Once they have done this, the effect will last a very long time
• If you do not want a protein to be produced in cancerous cell
- You can use a piece of RNA to bind to the gene of that protein = no production of that protein
• siRNA = small interference RNA
- same concept but double stranded
- so, it is a bit more stable
• However, for RNA therapeutics the technology isn’t mature yet
- The problem is sending the RNA to the right place to silence the gene (no specificity)
- But once the RNA is there = long duration of action (advantage)
