Lecture 14 Flashcards
Uses of antibodies in therapy
Cancer (antibodies as magic bullets e.g. anti-CD52 which are found on white blood cells)
Examples of successful antibodies to treat cancer
-CD20 antibodies such as rituximab which recognises B cells. It’s a good acitivator of complement and ADCC
- Anti-Her2 antibodies (herceptin) which recognises Her2. The antibody locks the receptor, stopping the tumour from growing but it can evoke ADCC
Which antibodies deplete leukocytes and their uses
Antibodies to CD52, CD3, CD4 to help with organ transplantation and treating graft vs host autoimmune diseases
Which antibodies help with blocking cytokines
Antibodies to TNF-alpha, IL-1, IL-6, complement
What can immune checkpoint inhibitors do
T and B cells can be switched off. Such as antibodies to CTLA-4 (expressed by t cells once) and PD-1 (expressed by many)
How do cancers subvert immune responses
By down regulating the cells that expect to kill them. For example producing cytokines including Tregs and expressing checkpoint inhibitors
what does PD-1 interact with
PD ligands which are often presented on tumour cells which switches them off.
What can CTLA-4 and PD-1 act as
Immune checkpoints which are useful in dampening immune responses and exploiting cancer cells
Order of efficiency
Complement activations: IgGe -> IgG1 -> IgG2
Fc receptors on phagocytes: IgG1 = IgG3 -> IgG4
Fc receptors on NK cells: IgG1 = IgG3
FcRn (determines half life which is important in prolonging all subclasses)
What can modifications of Fc region allow
Can promote binding to neonatal Fc receptors which increases half life
What dpes C1Q bind to
Binds to the hinge going into the CH2 domains
What is FcyR1 and FcyR2
“lower hinge” which is important in phagocytes
What is fCRYr3a found on
Natural killer cells
what does FcryRN involve
Regions between the ch2 and ch3 domains - could mutate these and improve the properties of antibodies.
What does glycoengineering allow
Allows us to engineer the carbohydrate rather than the protein
What does removal of fucose improve
Removal of fucose at conserved asparagic 297 residue improves the IgG interaction with FcyR2 which improves ADCC.
How can we improve antibodies for therapy
Improving the properties of antibody by protein or glyco-engineering to improve half life (by improving or removing effector functions).
Alterations of glycolysation of IgG can improve interaction with FcRN (increasing half life) and interaction with FcR on NK cells
Glycolysation of Fc receptors influences effector functions and half life
What can antibody fragments be useful for
Sometimes big antibody fragments are hard to get into solid tumours
How does Bi-specificity work
Bi-specific antibodies consist of 2 fabs in different targets that bring effector cells close to the cell you want to kill
Modifications in bi-specificity
Fab fragments and single chain antibodies (smaller antibody fragments may enhance phamacokinetic properties compared to full length antibodies.
What does Fragment antigen binding consist of
A variable domain and the first constant region of each heavy and light chain
What do Single chain variable fragments consist of
Light chain and heavy chain variable regions joined by a linker peptide
Passive immunisation for COVID
Covalescent sera had limited efficiacy.
Monoclonal antibodies to SARS cov-2 consisted of Sotrovimab
Advantages of passive over active immunisation
- Immediate protection (up to 4 weeks)
-Suitable for immunocompromised patients
-May relieve sever symptoms
Disadvantages of passive immunisation
No long-lasting protection
Not very effective against latest variants
May promote escape mutants
Expensive to produce and administer
Future prospects for antibodies
Antibodies to conserved epitopes
Coctials of antibodies to different or bi-specifics
What antibodies can be used to treat excessive inflammation
Anti-interleukin 6 receptor (Toxilizumab)
Anti-C5a (Vilobelimab)
Car-2 t cells (chimeric antigen receptors)
T cells can be engineered to recognise tumour antigens
Treats acute leukocute lymphocytic leakemia
T cells are isolated from patients tumour
They’re engineered in vitro to express a chimeric antigen receptor
CD19 is fused to signalling domains which contain ITAB motifs (when reinjected it will bind to CD19 on tumour cells and t cells will become active)
Immunotherapy in the future
- Soluble t receptors
- Cancer vaccines (induce immune responses against tumour)
-tumour infiltrating lymphocyte therapy
-Gene editing of antibody genes in vivo (CrispR Cas9)- engineering the immune response to produce antibodies of the right type
-Modulating innate immune cells - macrophages tend to be immunosuppressive
-Use of gamma delta T cells for cancer
