Session 4 - Lecture 1 - Monoclonal Antibodies Flashcards
1 - CLINICAL USE OF MONOCLONAL ANTIBODIES
CLINICAL USE OF MONOCLONAL ANTIBODIES
“Consultant haematologist with a specialist interest in lymphoma – we use a lot of mAb - use immunology every single day in how I manage my patients”
2 - Learning objectives
- To illustrate the use of monoclonal antibody therapy in patients
- A bit of history
- Classes of monoclonal antibodies
- Use in lymphoma as an example
- What impact does this have on patients?
“2. bg
- different types
- of how mAb have really transformed pt care over the last 15-20 yrs”
4 - Nobel Prize in Physiology or Medicine 1901 and 1904
The Nobel Prize in Physiology or Medicine 1901
“for his work on serum therapy, especially its application against diphtheria, by which he has opened a new road in the domain of medical science and thereby placed in the hands of the physician a victorious weapon against illness and deaths”
“You see we must take aim - aim by chemical variation! The marvellous effect of an antibody in the serum is due to the fact that in no case it has affinity for the body substances but flies straight onward without deviation, upon the parasites.
The antibodies are therefore MAGIC BULLETS which find the targets themselves… we must therefore concentrate all our powers and abilities on making the aim as accurate as we can contrive, so as to strike the parasites as hard and the body cells as lightly as possible.”
circa 1904
“von Behring 1901 - discovered if u inject animals with a toxin, then those animals mount an immune response. He wud do this with horses, give them diptheria, take the blood from the horses, isolate the serum which would be enriched with the antitoxins that the horse had developed against the diptheria. Actually given to pts in early 1900s with pretty impressive clin outcomes.
Dr Paul Ehrlich – postulated idea that cells in our bodies can develop chemical structures which could bind to toxins, almost like a lock and key – and what’s more is that these cells could release these chem structures into the circulation [magic bullets] – he proposed could seek out toxins anywhere throughout body with exquisite specificity – only now we’re realising potential that Ehrlich first described in 1904.”
5 - What are monoclonal antibodies?
Antibody (immunoglobulin secreted by B cells)
- variable region of heavy chain
- Fv
- variable region of light chain
- Fc
- hypervariable regions
- VH
- VL
- CH1
- CL
- Fab
- hinge
- CH2
- CH3
Antigen (foreign substance that stimulates antibody production)
- Epitope (antibody binding site)
- Paratope: antigen-binding site
- hypervariable regions of heavy chain
- hypervariable regions of light chain
Evolution and Emergence of Therapeutic Monoclonal Antibodies, Volume: 127, Issue: 22, Pages: 2222-2230, DOI: (10.1161/CIRCULATIONAHA.113.002033)
“Magic bullets = antibodies. Chem structure here – originally described, we’ve learnt a lot more in 100 years.
So this is an antibody (Ab), which comprises a heavy and a light chain, can divide the Ab into two parts
- Fab domain: Ab binding fragments
- Fc region: crystallisable region that binds to other elements of the immune system.
So Fab region binds to antigens; within Fab region are hypervariable domains, which essentially enable Abs to recognise an almost unlimited number of pathogens or antigens.
Antigen = protein which elicits an immune response Epitope = part of the antigen that actually binds to the Ab; the antigenic determinant of the protein.
So we’re talking about mAbs, so these are Abs, but they can be polyclonalAb or monoclonalAb. MAb are monovalent which means they only have affinity for a single protein, whereas pAb have affinity for different types of protein.”
https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.113.002033
p3
6 - Monoclonal antibodies in clinical practice
Monoclonal antibodies in clinical practice • Diagnostics - Signal - Light - Fluorescent Tag - Labeled Primary Antibody - Proteins Cell/Tissue • Therapeutics - HUMIRA PEN adalimumab - Rituximab RITUXAN - Trastuzumab HERCEPTIN
“So 100 years later how are these magic bullets impacted broadly to clinical care? We can divide that into 2 broad aspects: diagnostics and therapeutics. We know that mAbs can tag a specific cell receptor on a cell, so we can use that in diagnostics: if we add a bit of chemistry to the Ab, when that Ab tags the cell receptor of interest, it can either emit a light signal, which can be read by a detector, or it can cause a chemical reaction that results in a coloured reaction to occur. So this is what pathologists use every day in the hospital, so this is a thin section of a biopsy that’s been taken from a pt - without any stains it’ll just look blue – you can see cell shapes and size, can comment on that, but you wouldn’t be able to confidently say exactly what type of cell that was. But if we add antibodies, and if that binds to cell, tells us there’s a cell surface receptor there that locks into the Ab. And then you add your chemical reaction, and in this example, the cells turn brown if target is present: this is CD20 – here we get lots of CD20 stains - that would tell the pathologist these are mature B cells, which can start to refine the diagnosis. So for lymphoma, you’d do anything between 10-20 of these antibody stains: 10 or 20 cuts, put on your antibodies, no T cells, no B cells, this and that and then come up with diagnosis. In diagnostics we also use mAbs, pregnancy tests (Clearblue is based on a mAb) – blood grouping to find out whether someone is A, B, or O etc.: all based on mAbs. Other big area is treatment, what we’re going to move onto now - how Talk about how mAb is used to treat pts.”
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