Biologic drug examples Flashcards
What kind of drug is Humira?
Monoclonal antibody
What are the sizes of Humira’s light and heavy chains?
Light chain: 24 kDa
Heavy chain: 49 kDa
(pls put this in the cheatsheet)
How does Humira differ from infliximab if they target the same antigen?
- Humira has a human variable region while Infliximab has a mouse variable region so humira is less immunogenic
- Humira has a half life of 10-20 days while infliximab has a half life of 8-10 days
What is the disease indication of Humira and how does it work?
- Inflammation
- Normally, TNF alpha (inflammatory cytokine) binds to TNFR 1 in the cell membrane
- Humira binds to TNF alpha and prevents it from binding to TNFR, reducing inflammation
What are the side effects of Humira?
Its immunosuppressive nature can lead to serious infections such as Tuberculosis.
What is another name for Keytruda?
Pembrolizumab
What kind of drug is Keytruda?
Monoclonal antibody
It’s an immune checkpoint inhibitor
What is the mechanism of action of Keytruda?
- Normally, PD-L1 on the tumour cell will bind to PD-1 on the T cell to inactivate it
- Keytruda binds to PD-1 on the T cell, preventing the tumour cell from inactivating the T cell
- This way the TCR can bind to MHC on the tumour cell and recognise and kill
What are the challenges associated with the use of Keytruda
- PD-L1 expression levels not always a definitive indicator of how well Keytruda will respond to the cancer
- Combination therapy
- ‘Cold’ tumours do not respond well to Keytruda
- The high costs of Keytruda make it inaccessible to patients
How did Avastin come about?
- In 1993 they discovered that inhibiting Vascular endothelial growth factor (VEGF) suppresses angiogenesis and tumour growth in mice
- In 1997 they developed Avastin
How does Vascular endothelial growth factor (VEGF) promote tumour progression?
- Prevents apoptosis of tumour cells
- Impair maturation and function of dendritic cells and T cells
- Promotes cancer cell proliferation
- Stimulates migration of cancer cells via metastasis to other areas
- Stimulates the proliferation and survival of endothelial cells of blood vessels
- Increases the permeability of vessels
- Stimulates the formation of new blood vessels to the tumour
How does VEGF cause angiogenesis?
- The tumour sends out high amounts f VEGF, which binds to the VEGF receptors on endothelial cells inside blood vessels
- Bloof vessels grow toward and within the tumour, supplying it with oxygen and other nutrients, allowing the tumour to grow more
What is the other name for Avastin?
Bevacizumab
What kind of drugs can Avastin be combined with to increase the anti cancer effect?
Checkpoint inhibitors like Atezolizumab, which result in tumour cell death
What is Kymriah and what is it used to treat?
CAR-T therapy that is used to treat blood cancers: Leukaemia and Lymphoma
(Kymriah is the name of the therapy itself, it’s not a drug or anything, and it targets cytotoxic T cells)
What is Leukaemia and Lymphoma?
Leukaemia: WBC cancer originated from the bone marrow
Lymphoma: WBC cancer originated from the lymphatic system
What is the target of Kymriah?
It targets the CD19 pan-B-cell marker on B cells
What are the pathways by which these CAR T cells kill cancerous cells?
- The T cell will secrete perforin and granzymes: perforin creates pores in the target cell’s membrane, allowing granzymes to enter and initiate apoptosis
- The T cells increase cytokine production which kills the tumour cells ?? idk
What are the challenges of Kymriah therapy?
- Extremely high costs (>1.5 mil. USD)
- Cytokine release syndrome, which can have a severe reaction –> the activation of T cells can release cytokines that activate bystander immune cells and non immune cells that also release cytokines, causing a cytokine storm
- This can cause High fever, nausea, Headaches and rashes
- Or more severely, can cause cardiovascular Shock, Cardiac Arrhythmia, Pulmonary Edema, Organ Failure and potentially death - The entire process takes 21 days, by that time the patient might be dead
- Contaminants
What are the alternatives to autologous CAR T cells (in Kymriah) and how might they mitigate the challenges?
Allogenic CAR T cells that come form a donor
Advantages over autologous CAR T:
1. Scaled up industrial process so you can produce a large amount of this from one donor
2. Lower waiting time???
3. Much lower costs
What is the purpose of next generation sequencing?
- Next-generation sequencing (NGS) is used to identify mutations specific to tumor cells by sequencing patient normal DNA, tumor DNA, and tumor RNA
- The DNA sequences of the mutations are determined through this process
- Tumor-specific mutations lead to the expression of neoantigen proteins from mRNA that are highly expressed on tumor cells
What is the last step of next generation sequencing and what is it needed for?
The last step of NGS is Human Leucocyte Antigen (HLA) typing to determine the binding affinity of the neoantigens to the specific MHC molecule of the patient. Stronger binding allows more effective presentation to T-cell receptors for an immune response
What are the disadvantages of treatments like Keytruda over treatments that involve neoantigen proteins produced by next generation sequencing?
Current treatment like Keytruda enables a better immune response to cancerous cells by removing inhibition of the immune response, but can cause adverse immune responses to the body’s own cells
What kind of drug is Aduhelm?
A high-affinity, igG1 monoclonal
antibody against a conformational
epitope found on Aβ
Explain the pathology of Alzheimer’s disease.
- The Tau proteins in the neurons misfold and form neurofibrillary tangles which disrupt neuron function
- The Beta amyloid proteins accumulate to form highly insoluble extracellular beta amyloid plaques which disrupt neighboring nervous cells
What disease is Aduhelm meant to target?
Alzheimer’s disease
What is the mechanism of action by which Aduhelm can treat Alzheimer’s disease?
- Aduhelm binds to a specific epitope in beta amyloid oligomers and fibrils
- They target beta amyloid aggregates for microglial mediated removal
- Removal of amyloid plaque within the brain slows down the progression of Alzheimer’s
What type of drug is Kadcycla?
Monoclonal antibody conjugated to a chemotherapy agent
What disease does kadcycla (T-DM1) treat?
Breast cancer
What are the 3 main mechanisms by which kadcycla (T-DM1) can prevent the growth of breast cancer cells
- Direct cell killing
- Cell growth prevention (by inhibiting HER2 signalling pathways)
- Antibody-dependent cell-mediated cytotoxicity (ADCC)
How does Kadcycla (T-DM1) inhibit HER2 signalling pathways, and whats the effect?
- Block the dimerisation of HER2 receptors to inhibit cell cycle progression
- Block cleavage of the extracellular HER2 domain, which downregulates the growth and division signallings
How does Kadcycla (T-DM1) mediate cytotoxicity?
It mediates the binding of an immune cell to the HER2 dimer, causing cell death
HER2 –> T-DM1 –> immune cell recepttor
What kind of drug is Herceptin
Monoclonal antibody
What is another name for Herceptin, and what does this tell us about the nature of the antibody?
Trastuzumab
Humanized antibody
What disease does Herceptin treat, and what is the target of Herceptin?
- Treats Breast cancer
- Binds to HER-2 receptor on breast cancer cells
What kind of protein is HEr-2
Its an epidermal growth factor receptor, and is overexpressed in breast cancer cells
How does Herceptin work?
Herceptin binds to the HER2-receptor on the C-terminal of domain IV (extracelluar)
2 major known mechanisms of action:
1. Interference of HER2 dimerisation: Binding facilitates endocytosis of the receptor-antibody complex, disrupting dimerisation
2. Antibody Dependent Cell Mediated Cytotoxicity (ADCC): Mediates the binding of the tumour cell to a natural killer cell, which releases perforin and granzymes to kill the tumour cells
What is a limitation of Herceptin?
- HER2 specificity: Almost 80% of breast cancer patients are ineligible for Herceptin due to HER2-negative status.
- Limited Potential - Most breast cancer
patients cannot benefit from Herceptin - Importance of HER2 Testing for patient HER2 status determination, as it ensures appropriate selection for
Herceptin therapy
What kind of drug is Blinatumomab?
Monoclonal antibody
What is the mechanism of action of Blinatumomab?
- Blinatumomab binds to both CD3+ on T cells and CD19+ on malignant B cells
- The binding causes an immunologic synapse
- The T cells release perforin and granzymes, which cause the lysis of tumour B cells
What kind of drug is BNT111?
mRNA vaccine
What is the mechanism of action of BNT111?
- Administered by IV
- Enters dendritic cells by endocytosis and it’s (TAA) antigen is presented on the surface by MHC
- CD4+ and CD8+ cells bind to it –> perforin and granzymes –> dead
What are the limitations of BNT-111?
- Inflammatory effect
- TAA antigen specificity because they are expressed in both cancer cells and normal cells
- Tumour heterogeneity
What kind of drug is imlygic?
Oncolytic viral gene therapy
What is the mechanism of action of imlygic?
- It selectively infects and kills cancer cells
- Also increases immune recognition of cancer cells
- The resulting oncolysis releases a lot of tumour antigens which can be immediately ingested by the surrounding dendritic cells
What kind of drug is Yescarta?
Its a CAR T cell therapy
What disease does Yescarta treat?
B cell lymphoma
What are the limitations of Yescarta?
- Can cause cytokine release syndrome, where the immune response releases a lot of inflammatory cytokines
- Administration challenges
What kind of drug is Yervoy?
Monoclonal antibody
What is another name for Yervoy?
Ipilimumab
What is Cytotoxic T-lymphocyte
associated protein 4 (CTLA-4) and when was it discovered?
- Immune checkpoint protein expressed on T cells which transmits inhibitory signals
- Downregulates immune response and prevents autoimmune diseases
- Discovered around 1991-1995
What is the mechanism of action of Yervoy?
- It binds to CTLA-4 and stops the inhibitory signals, so that the T cell is active.
- The activation of cytotoxic T cells enables them to recognize and target cancer cells, leading to an immune-mediated destruction of the tumor.
