The changing face of therapeutics Flashcards
What are monoclonal antibodies?
members of the Ig superfamily
IgG 1-4 with different constant domains
Which mab is mainly used in therapies
IgG1 or 3
IgG 1 has good antibody binding
How many types of monoclonal antibodies are there?
4 types
Murine (-omab)
Chimeric (-Ximab)
Humanised (-zumab)
Human (-umab)
What are the mechanisms of therapeutic antibodies?
Give an example drug for each mechanism
Cytokine & growth factor blockade
Ligand blockade
Receptor blockade
Receptor downregulation
Depelting and signalling antibodies
Weaponised antibodies
Bispecific antibodies
Neutralising and blocking antibodies
Ligand blockade: infliximab - a recombinant humanized monoclonal antibody hand binds soluble TNF alpha
Receptor blockade: Tocilizumab - a recombinant humanized monoclonal antibody IL-6 receptor inhibitor used to treat autoimmune conditions
Receptor downregulation: Efalizumab - a recombinant humanized monoclonal antibody binds to CD11 receptors on T lymphocytes
Depleting and signalling antibodies:
Antibody-dependent cell mediated cytotoxicity (ADCC)
Antibody-dependent cellular phagocytosis (ADCP)
Complement-dependent cytotoxicity (CDC)
Explain the neonatal fragment crystallisable (Fc) receptor FcRn
Antibodies (e.g. IgG and albumin) have long plasma half lives
Ingested via pinocytosis
Once ingested they bind to the neonatal fragment crystallisable receptor (FcRn)
But only binds to the FcRn when its acidic (pH 5.0-6.5) [not in its physiological pH 7.4]
acidification = FcRn binds IgG (and albumin)
Retained within endosome
FcRn bound IgG os transported back to the plasma membrane
Vesicle exocytosis =IgG is released into circulation
What is Myasthenia Gravis?
Autoimmune disease caused by IgG against alpha 1 subunit of the nicotinic acetylcholine receptor in neuromuscular junctions
Causes loss of motor activity
Initial stages treat with cholinesterase inhibitors
No disease modification
State a drug treatment for Myasthenia Gravis
Efgartigimod (VYVGART)
Efgartigimod MOA
FC Frgament (pH independent to FcRn) > binds to receptor > Lowers IgG and blocks IgG transfer across barriers
Weaponised antibodies (oncology)
-Radioactive element delivers a short range burst of radiation to cells targeted by the antibodies
or
-Chemical linkage to a bacterial toxin
Bispecific antibodies
Multiple functionally different binding domains that allow for interaction with two target antigens
State the strengths and weaknesses of antibodies
Strengths:
High success rate
Well tolerated
Generally specific (less off target effects)
Limitations:
Expensive with high production costs
Limited penetration to CNS
Cannot be administered orally
What are the benefits of using nanobodies?
Robust binding molecules (more potent)
Chemical and thermal stability
Better penetration into tissues and organs
State the types of dysfunctional proteins
Poor translation
Truncated protein
Protein that doesn’t go where its supposed to
Protein does not function
Excess protein