Download What is a drug?

Drugs that influence immune function
Dr. Andrew Wiemer
What is a drug?
• A substance which has an effect when introduced into the
body.
– Substance – small molecule, macromolecule
– Effect – therapeutic, prophylactic, recreational, performance
enhancing
– Body – a human, (or veterinary, or pathologic)
What happens to a drug?
• Pharmacokinetics
– What is the fate of drug after
administration?
• Pharmacodynamics
– How does the drug affect the
body?
https://gostardb.com/gostar/images/pharmacodynamicpharmacokinetic.jpg
Drug targets are most often receptors
• Classic receptor is on cell membrane
– May also be intracellular or nuclear
• Receptor binds to a ligand (agonist), which initiates a
response
• Can be non-receptors
– Enzymes
– Structural proteins
– Nucleic acids
Four major types of receptors
Ion
channels
(~13%)
G protein
coupled
receptors
(~27%)
Receptor
tyrosine
kinases
(<2%)
Nuclear
receptors
(~13%)
http://pharmacologycorner.com
Drugs can be classified based on their
dosing, substance, or targeted species
• Most current drugs are small molecules, but the fastest
growing group of drugs is biologicals
• Most biologics are immune related
• Most drugs target humans, but some target pathogens
• Most drugs are orally administered
Overington et al., Nat Rev Drug Disc, 2006
Immunological drugs
• Two broad approaches
1. Alter the function of immune system cells
2. Use the immune system to produce drugs
Why alter function of immune cells?
• Activate an immune
response
– Infectious disease
– Cancer immunotherapy
• Inhibit an immune response
– Organ transplant
– Autoimmune disease
T cell activation
Rudd, Nature Reviews Immunology 8, 153-160
9
T cell receptor signaling
Adhesion molecules
Receptors
Co-receptors
Relevant drug target
Enzymes
cytokines
Vaccines
https://apps.nlm.nih.gov/againsttheodds/exhibit/preventing_disease/role_of_science.cfm
Vaccines
http://hcrc.missouri.edu/2015/08/12/the-power-players-in-public-health/
Vaccines
http://hcrc.missouri.edu/2015/08/12/the-power-players-in-public-health/
Checkpoint therapy
• Seeks to overcome normal
inhibitory signaling that
prevents T cell activation
• Ipilimumab – antibody to
CTLA4 that breaks tolerance
in cancer (FDA approved
2011)
• Nivolumab – antibody to
PD1 (FDA approved in 2014)
http://www.onclive.com/publications/contemporary-oncology/2014/February2014/Immune-Checkpoint-Blockade-in-Cancer-Inhibiting-CTLA-4-and-PD1PD-L1-With-Monoclonal-Antibodies
Transplant/immune disease
Small molecule inhibitor
• Cyclosporine (aka Neoral,
Sandimmune, Restasis)
• Immunosuppressant used in
organ transplant
• Also used in psoriasis,
asthma, dry eye
• Prevents dephosphorylation
of NFAT, blocking T cell
proliferation and cytokine
production
Cyclosporine
Transplant/immune disease
Antibody inhibitor
• Muromonab-CD3 (OKT3)
• Used in organ transplant
• First monoclonal Ab
approved for therapeutic
use (1985)
• Incorrectly activates T cells,
preventing them from
responding to graft
Why use products of immune system as
drugs?
• Cytokines
– Advantages
• Boost immunity towards
disease such as cancer
– Disadvantage
• Narrow therapeutic window
– high doses can be toxic
• Antibodies
– Advantages
• Specificity to target
• Speed of production
– Disadvantages
• Oral dosing difficult
• Trouble with intracellular
targets
Cytokines
• Proleukin (FDA approved
1992)
• Synthetic version of human
IL-2
• Promotes proliferation of T
cells, which can then kill
tumor cells
Therapeutic antibodies
• Natalizumab (Tysabri) is
an antibody to the
integrin CD49d
• Approved for treatment
of multiple sclerosis (MS)
• Prevents infiltration of
immune cells into brain
• Prevents migration
across surfaces
expressing VCAM such as
endothelial cells
http://www.rxlist.com/tysabri-drug/clinical-pharmacology.htm
Therapeutic antibodies
• Cetuximab
• Representative of a class
of antibodies that target
growth factor receptors
• Binds to extracellular
domain III of EGFR
• Blocks ability of EGF to
bind EGFR
• Prevents formation of
extended conformation
• Inhibits dimerization and
autophosphorylation
Li, 2005, Cancer Cell
Therapeutic antibodies
• Adalimumab (Humira)
• Binds to soluble TNF alpha,
preventing it from binding
its receptor
• Useful for treatment of RA,
Crohn’s disease, psoriasis
http://www.haderermuller.com/portfolio-item/inflammatory-bowel-disease/
Antibody drug conjugates
• Brentuximab vedotin
• Approved for lymphoma
therapy
• CD30 antibody
• Monomethyl auristatin E
• Cathepsin cleavage to
activate
Therapeutic antibodies
• Summary
– At least 5 different ways that
monoclonal antibodies can
function are shown here
– All are extracellular targets
– See Janeway Chapter 16?
(manipulation of the immune
response)
Nature Reviews Immunology 10, 301-316 (May 2010)