Immunology 06. Antibody Immunotherapy Flashcards
Antibody Drug Nomenclature
Murine: -[…]mab
Chimeric: -[…]mab
Humanized: -[…]mab
Fully Human: -[…]mab
Antibody Drug Nomenclature
Murine: -omab
Chimeric: -ximab
Humanized: -zumab
Fully Human: -umab
E.g generic name for HUMIRA is adalimumab, so that tells us that it is fully human ab.
Well, if this comes out for MCQ/MEQ, that will be quite funny
OXIZUU
How are 90-95% humanized antibodies obtained from mouse antibodies?
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How are 90-95% humanized antibodies obtained from mouse antibodies?
CDR Grafting
CDR = Complementarity Determining Region
How are fully human antibodies derived for fully human antibody immunotherapies?
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How are fully human antibodies derived for fully human antibody immunotherapies?
From individuals who have an unusual auto-immune repertoire
For example, HUMIRA, a fully human anti‐TNF antibody, was derived from a patient who was making an auto‐antibody response against her own TNF.
Well you technically can immunize patients with the antigen of interest to get the antibody of interest, but that is just completely unethical!!!
Bruh not trivial card. Came out for M2 Pros 19/20
How was the HAMA challenge solved?
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How was the HAMA challenge solved?
Chimerization/Humanization/Make Abs directly from human patients
Using principles of protein engineering!! Smort.
Not a trivial card. Can come out in MEQ….
Is serum immunotherapy polyclonal or monoclonal?
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Is serum immunotherapy polyclonal or monoclonal?
polyclonal~
e.g treatment of diphtheria and tetanus in the 1890s-1920s using polyclonal mixture of antibodies in animal serums that are specific for a pathogen to treat patients.
“The serum used, contained huge quantities of non‐specific antibodies plus animal complement and stress factors. A common side‐effect of this form of therapy was an acute rheumatoidlike reaction presenting as swollen joints and inflamed kidneys ‐ this is termed serum sickness.”
Outline the 2 methods of humanizing mouse monoclonal antibodies.
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Why is this necessary?
Humanizing the antibody is necessary as mouse (and other animals) antibodies is recognized by human immune system as foreign, resulting in the production of human anti-mouse antibodies (HAMA) that can neutralize the mouse antibody. This means that the mouse antibody will only have good efficacy on its first administration but subsequently will lose its activity, and that is not ideal especially for chronic diseases (and cancer) which requires multiple administrations over extended periods of time to treat
Outline the 2 methods of humanizing mouse monoclonal antibodies.
Humanization of mouse antibodies involves cloning and pasting Complementarity Determining Regions (CDR) from a mouse antibody onto a human antibody scaffold. There are 2 ways to do this:
- CDR Grafting: CDR regions from mouse heavy and light chain genes grafted onto human antibody scaffold. But within each CDR region there are aminoacids that cannot be changed from mouse to human without compromising specificity of resulting ab, so the resulting antibody is 90-95% human (humanized).
- Fully human Ab from patients: Identifying individuals with antibody repertoire of interest (eg patient with anti-TNF antibody against his/her own TNF), isolate the ab secreting cell followed by cloning. Resulting antibody is 100% human
Why is this necessary?
Humanizing the antibody is necessary as mouse (and other animals) antibodies is recognized by human immune system as foreign, resulting in the production of human anti-mouse antibodies (HAMA) that can neutralize the mouse antibody. This means that the mouse antibody will only have good efficacy on its first administration but subsequently will lose its activity, and that is not ideal especially for chronic diseases (and cancer) which requires multiple administrations over extended periods of time to treat
4 marks in M2 Pros AY19/20
Outline the 2 methods of humanizing mouse monoclonal antibodies.
Humanization of mouse antibodies involves cloning and pasting Complementarity Determining Regions (CDR) from a mouse antibody onto a human antibody scaffold. There are 2 ways to do this:
- CDR Grafting: CDR regions from mouse heavy and light chain genes grafted onto human antibody scaffold. But within each CDR region there are aminoacids that cannot be changed from mouse to human without compromising specificity of resulting ab, so the resulting antibody is 90-95% human (humanized).
- Fully human Ab from patients: Identifying individuals with antibody repertoire of interest (eg patient with anti-TNF antibody against his/her own TNF), isolate the ab secreting cell followed by cloning. Resulting antibody is 100% human
Why is this necessary?
[…]
Why is this necessary?
Humanizing the antibody is necessary as mouse (and other animals) antibodies is recognized by human immune system as foreign, resulting in the production of human anti-mouse antibodies (HAMA) that can neutralize the mouse antibody. This means that the mouse antibody will only have good efficacy on its first administration but subsequently will lose its activity, and that is not ideal especially for chronic diseases (and cancer) which requires multiple administrations over extended periods of time to treat
What are 2 example of a chimeric monoclonal ab that are approved?
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What are 2 example of a chimeric monoclonal ab that are approved?
**- Rituximab/Rituxan (anti-CD20) –> B cell lymphomas
- Infliximab (anti-TNF alpha) –> RA
CD20 is a B-cell marker. Anti-CD20s depletes B cells that rise from the B cell lineage (e.g non-hodgkins lymphoma)
TNF alpha is a key inflammatory cytokine that drives much of the pathology associated with Rheumatoid Arthritis
What are 2 examples of polyclonal serum immunotherapy still used in medicine today?
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What are they used for?
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What are 2 examples of polyclonal serum immunotherapy still used in medicine today?
- HBIG (Hep B ImmunoGlobulins)
- IVIG (IntraVenous ImmunoGlobulins)
What are they used for?
- HBIG: reduce verticle transmission of Hep B virus from infected mother to newborn child
- IVIG: auto-antibody mediated cytopenias (kawasaki disease,etc)
Compared to the serum immunotherapy used in 1890s, modern serum immunotherapy involves purification of these polyclonal antibodies so adverse effects are less severe (but still have). Medicine is alw about balance mah….
What is the difference between polyclonal and monoclonal antibodies?
Polyclonal: […]
Monoclonal: […]
What is the difference between polyclonal and monoclonal antibodies?
Polyclonal: a mixture of antibodies that target multiple epitopes on the same antigen
Monoclonal: a single antibody that targets a single epitope on the antigen
Need to recognise that a single antigen has multiple epitopes
And that monoclonal is the better choice most of the time
What is the principal side-effect to monitor for ALL antibody therapeutics?
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What is the principal side-effect to monitor for ALL antibody therapeutics?
development of allergy-like reactions and anaphylaxis
This is due to the intrinsic pro-inflammatory nature of the Ab biologic drug
Why mouse antibodies (eg. CAMPATH) have good efficacy on the first administration but loses its activity subsequently?
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Why mouse antibodies (eg. CAMPATH) have good efficacy on the first administration but loses its activity subsequently?
Antibody responses –> HAMA!!
HAMA = Human Anti-Mouse Antibodies
Patient makes own host antibody response (HAMA) against the mouse antibodies (foreign protein antigen), and neutralizes these mouse antibodies, blocking their activity.
Endogenous = growing or originating from within an organism
Heterophilic =having an affinity for an antigen other than its specific antigen
