Intro to biologics Flashcards
What are biologics
They are medicinal products that involve living sources, e.g., protein-based therapeutics (e.g., peptide hormones, antibodies, engineered proteins), gene/cell therapies (stem cells and transplants), vaccines, blood products, diagnostic reagents.
Insulin is a biologic that was first isolated from bovine pancreas in the 1920s and then the first med to be synthesised by recombinant DNA technology in the 1980s. due to size has to be injected and has some risk of immunogenicity
Advantages of protein therapeutics
May be difficult to make small molecule drugs for the target.
better affinity and selectivity.
More diverse mechanism of action, e.g., targets a secondary messenger molecule
disadvantages of protein therapeutics
Lack of efficacy from PK. needs to be injected and poor permeability to certain tissues, e.g., BBB
Species variations in protein sequences - lack of efficacy in non-human biologics
potential immunogenicity - humanised TGN1412 antibody developed for autoimmune diseases due to anti-CD28 antibody activity (activates T-cells without T-cell receptor activator). in animal studies saw T-cell down regulation and release of antiinflammatory cytokines. in humans led to cytokine storm due to activation of immune system. animal studies did not predict this effect.
complex manufacturing process that is difficult to reproduce and get high purity
Types of antibodies
Contain heavy and light chain which form the antigen binding site. variable regions of the heavy and light chain determine the binding. The constant region are areas of the antibody that do not change. parts of the chains.
The Fab is the antigen binding fragment domain - region that recognises antigen.
can be formed monoclonal or polyclonal. -mab signifies monoclonal. polyclonal uses many different IgG molecules that have high affinity for the antigen. monoclonal uses isolated B-cells to produce identical IgG.
-momab (murine), -ximab (chimeric), -zumab (humanised), -umab (human)
How antibodies are created
Murine: inject mouse with antigen, created a fused cell line - immortal that produces antibodies. then purify antibodies.
Chimeric produced by taking the mouse target sequence and attaching it to human Ab
To create humanised, the mouse binding sequence is integrated into a human Ab
human antibodies produced using a transgenic mouse that produces human Abs and then the antigen is injected.
Humanised and human antibodies less likely to produce an allergic response
Phase libraries can be used to make human Ab. they take the mRNA from a patient with the disease and express it in bacteriophages. the bacteriophages then express antibodies on their surface. this creates a library of antibodies that are then screened to identify the best Ab.
a single B-cell from a human can be used to generate Ab. e.g., human with covid has their B-cells taken and antibodies isolated and purified. can be then given to others.
Mechanism of action of Abs
Commonly are receptor antagonists and enzyme inhibitors. bind to target and prevent agonist binding.
E.g., retuximab an EGF antagonist for neck, head, colon and lung cancers.
Can also target the growth factor, e.g., bevacuzimab which binds to VEGF and infliximab which binds to TNFa
Some antibodies can act as agonists for death receptors to induce tumour apoptosis, e.g., CDX-1140 as an Ab agonist for CD40 - currently in clinical trials. activates T-cells leading to T-cell mediated tumour regression. functions by binding to 2 death receptors mimicking their dimerisation - thus activating them
Antibodies can also contain a cytotoxic drug, where the antibody epitope binds selectively to tumour cells and then the cytotoxic component kills the tumour cells
Bispecific and trispecific antibodies exist. e.g., catumaxomab which targets CD3 and EpCAM. for tumours in patients with malignant ascites. Targets the T-cells to the tumour cell by binding both. This also binds to accessory cells such as macrophages and NK cells through its Fc region. this leads to phagocytosis of the tumour cells and cytokine release which activates the T-cells.
