L10: Biological drugs part 2 Flashcards
mechanisms of actions of antibodies
- autoimmune diseases driven by tnf-alpha. can use antibodies directed at it to sequester tnf-alpha to prevent it from activating your immune cells: adalimumab (anti-tnf alpha)
- transtusamab binds to the her2 receptorm a form of the ostrogen receptor and is used to treat breast cancers that are highly addicted to oestrogen.
- agoonist: dulaglutide helps treat obesity
take ligand of your receptor and fuse this to antibody so variable part of antibody is a ligand so can activate receptors (for agonists). - exploiting their natural functions
ADCC. cell lysis. rituximab (anti-CD20)
CDC-complement-dependent cytotoxicity - targeting: delivering toxin.radiation
tositumomab (anti cd20) - antibodies can also be used to treat infections (antisera)
regen-cov-anti-covid antibody cocktail: take antibodies from somone who recovered from covid. introduce to patient. antibodies will bind to the spike protein of your covid virus preventing it from binding to these ace receptors of your lung epithelial cells and wroking as a flag for your immune cells to recognise and neutralise the virus.
evolution of therapeutic antibodies?
Recombinant Antibody Technology and Humanisation
Early therapeutic antibodies were often made from mouse antibodies, which the human immune system recognised as foreign, leading to immune reactions that reduced their effectiveness.
To solve this, scientists used recombinant DNA technology to modify antibody structures:
Chimeric Antibodies:
Combine the variable region (which binds the target) from a mouse antibody with the constant region from a human antibody.
Result: about 65% human.
Example: Rituximab.
Humanised Antibodies:
Instead of using the entire mouse variable region, only the complementarity-determining regions (CDRs) — the parts that directly contact the target protein — are taken from the mouse.
The rest of the antibody is human.
Result: about 90–95% human.
Example: Ocrelizumab.
Fully Human Antibodies:
Created by genetically engineering mice to remove the genes that make mouse antibodies and insert human antibody genes instead.
These mice now produce fully human antibodies from birth, which are not seen as foreign by the immune system.
Result: 100% human.
Example: Ofatumumab.
This progression from chimeric to humanised to fully human antibodies has greatly reduced the risk of immune rejection and improved the effectiveness and safety of therapeutic antibodies.
next generation therapeutic antibodies
Antibody Engineering to Improve Delivery and Function
🧬 Modifying Size and Structure for Delivery
Full-sized antibodies are large molecules and can only be delivered intravenously.
For some treatments, you don’t need the whole antibody — just the part that binds the target (e.g. as an antagonist or agonist).
In these cases, smaller antibody fragments like Fab or F(ab’)₂ fragments can be used:
They are less likely to be recognised by the immune system
Can be delivered more easily (potentially via other routes like subcutaneous injection)
⚙️ Glycoengineering: Altering the Immune Response
The constant (Fc) region of an antibody is recognised by:
Immune cells (e.g. NK cells via Fc receptors)
Complement proteins (which trigger cell lysis)
In some therapies — like targeting cancer cells — antibody-dependent cellular cytotoxicity (ADCC) (immune cell-mediated killing) is preferred over complement-dependent cytotoxicity (CDC).
➡️ To bias the immune system toward ADCC, scientists use glycoengineering:
Glycosylation sites are modified to:
Reduce complement binding
Preserve or enhance binding to immune cells
🔁 This allows better control over how the body responds to the antibody, depending on the desired therapeutic outcome.
examples to remember
adalimumab: trade name- Humira Human antibody
nivolumab: Opdivo
Human antibody
pembrolizumab: Keytruda
Humanised Antibody
rituximab: Rituxan, MabThera
Chimeric antibody
cellular therapies
Bone marrow transplantation
Transfer of haematopoietic stem cells to treat blood cancers (Leukaemia, Lymphoma, Myeloma) and other blood disorders (anemia)
Patient’s own cells (autologous) or donor-derived (allogeneic)
Stem cell transplantation
Few approved uses
CAR T cells
Immune cells trained to kill
CAR T cells
Normal T cells have receptors that recognise foreign antigens and initiate an immune response. In CAR T-cell therapy, scientists engineer T cells to recognise and attack cancer cells more effectively.
🔬 What is a CAR?
A Chimeric Antigen Receptor (CAR) is an artificial receptor engineered into T cells. It combines:
An antigen-binding domain from an antibody (which binds to a specific target on cancer cells)
With signalling domains from a T-cell receptor, so the engineered T cell still activates like a normal T cell once it binds to the target
➡️ This allows T cells to recognise tumour-associated antigens that they wouldn’t normally detect.
Types of CAR T-cell Therapy
Autologous CAR T Cells
T cells are taken from the patient’s own blood
Genetically modified to express the CAR
Expanded in the lab until there are millions of CAR T cells
Then re-infused into the same patient
✅ No immune rejection (since cells come from the patient)
Allogeneic CAR T Cells
T cells come from a healthy donor
Can be manufactured in large batches — a “off-the-shelf” product
💡 More convenient and scalable, but…
⚠️ There’s a risk of immune rejection (host-vs-graft reaction)
Managing Immune Rejection
To reduce the risk of the patient’s immune system attacking donor CAR T cells:
Patients are treated with anti-CD52 antibodies
These antibodies deplete the patient’s normal immune cells, including T cells
This helps prevent Host-versus-Graft Disease (HvGD) and improves CAR T-cell survival
Example: CAR T Cells Targeting CD19
CD19 is a surface protein found on B cells, including cancerous B cells in B-cell leukaemia and lymphoma
CAR T cells engineered to recognise CD19 can specifically kill these cancer cells
advantages and disadvantages of biologicals
advantages: Highly specific, less off-target effects
Well-tolerated (as they look just like endogenous proteins)
Can perform functions that cannot be mimicked with small molecules
Replace proteins
Specifically activate immune cells to kill cancer cells
disadvantages: Biologicals are enormous
compared too small molecules
Poor absorption in gut
Need to be injected
Biologicals more complex
May be a mixture
Multiple functional domains
Can only target extracellular protein/molecule
Production via mammalian cells is a laborious and slow process
Costly
Small scale of production (few kg/year)
Shorter shelf-life
pharmacology of biologicals
Variable half-life
Short for insulin
Very long for therapeutic antibodies
Unquantifiable for cellular therapies
Clearance by intracellular lysosomal degradation
Efficacy may depend on proteins/cells of patient
Complement/Immune cells
Anti-drug antibodies
Patient T cells may be less functional
Safety
Less toxicity (only target-related adverse effects)
No drug-drug interactions
Increased immunogenicity (allergic reactions)
biologicals and regulatory status
Very difficult to generate products that are always the same
Batch-to-batch variation
Not all components of a biologic may be known
No time to characterise all possible components in a cell mixture
Production process must be the same every time, not the product
Production process part of the patent
Biosimilars, the generic variant of biologicals
Not necessary to be identical as long as safety and efficacy is the same
