Engineering Antibodies 2 Flashcards
When was rituximab first used?
1992
What was rituximab originally used for?
Follicular lymphoma - now used for all forms of B cell non-Hodgkins lymphoma
What type of antibody is rituximab?
Anti-CD20 - chimeric antibody
What is CD20?
A transmembrane glycoprotein found on developing B cells
What are rituximabs mechanisms of action regarding apoptosis?
Apoptosis
- turns on a intracellular signals (Cross linking CD20), leads to MAP kinase activation and calcium influx disturbing mitochondria
What are rituximabs mechanism of action for complement mediated cellular cytotoxicity?
Complement binds to antibody once it has bound to surface
What are side effects of rituximab?
Allergy
Infections risk - HSV, CMV etc.
Leukopenia
Dermatological/mucosal surface reactions
Gut and cardiovascular issues
Renal and respiratory issues
What are indications to discontinue rituximab?
JC virus is in the brain but suppressed in most people
Reactivation of hepatitis B and development of progressive multi focal leukoencephalopathy due to JC virus means discontinue rituximab
What are some other uses of rituximab?
Autoimmunity - rheumatoid arthritis
How does rituximab help with rheumatoid arthritis?
Helps remove auto reactive B cells
What are problems with rituximab used in rheumatoid arthritis?
Few problems - some risk of increased infections, poor response to vaccine, late-onset neutropenia, moderate drop in antibody levels
What happens if you take frucose groups off rituximab?
Does better ADCC
What is the fully human bio similar of rituximab?
Ofatumumab
What wasn’t worth carrying on with rituximab bio similars?
Anti-CD20 fragment bound to a different molecule to stabilise it, couldn’t compete with other biosimilars
What can omalizumab be used for?
Anti-IgE in asthma and allergy
What does omalizumab bind to and not bind to?
Binds to low affinity IgE receptor and free IgE
Doesn’t trigger mast cells
What is an example of a natural bio specific antibody?
IgE due to arm exchange
What are good engineered bio specific antibody examples?
Catumaxomab, blinatumomab and emicizumab
What are examples of use of bsAbs?
Cell-cell
Dual receptor interactions
Co-factor mimics
Piggybacking to target usually inaccessible sites
What does emicizumab bind?
Factor IXa and X
What does emicizumab do?
Replaces factor 8 in the clotting cascade , treatment for factor 8 deficient haemophilia A patients, reduces bleed events
What does blinatumumab do?
Treats B cell acute lymphoblastic leukemia
Supports T cell driven killing of tumour cells
What does blinatumumab target?
Has two light chains - one targets CD3, the other targets CD19
What are the two types of linker technology?
Cleavage - a peptide linker cleavable
Non-cleavable - releases after degradation of the antibody structure
What do antimitotics do?
Play with microtubules
Wbat does calicheamicin do?
Causes strand breakage in DNA
What does trastuzumab-emtansine do?
Targets HER2 receptor, causes mitosis arrest and cell death. Is a Microtubule inhibitor
What does gemtuzumab ozogamicin target?
Anti-CD33 for acute myeloid leukaemia
What does gemtuzumab ozogamicin do?
Conjugated to calcheamicin, it is released and reduced by glutathione into its active form and DNA stand breakages leads to repair mechanisms
