Ex. 2 L7: PK of Biological drugs Flashcards
What are biologics
Generally derived from living material (human, animal, microorganism)
Complex in structure and this not fully characterized
Biologics examples
Monoclonal antibodies (mAb) for in vivo use
-Monospecific antibody that is identical because they are produced by immune cells of a single type
-They are clones of a single parent cell (identical)
Cytokines, growth factors, enzymes, immunomodulators Proteins intended for therapeutic use that are extracted from animals or microorganisms
Other non-vaccine therapeutic immunotherapies
Vaccine, blood products and gene therapy
Mabs
Many people use MaB injections/drugs
More and more biologics on market
Monoclonal antibodies (mAb)
VERY Target specific
Companies LOVE MAbs – spend a lot of money on them
We do see side effects from exaggerated pharmacological effects = drug works too well, causes effects
Antibodies – Y shaped protein
unit: Nm
Thickness of membrane – it is impossible to diffuse into cell – NO PASSIVE DIFFUSION DUE TO SIZE
Small molecule drugs
Small molecule drugs go everywhere because they can diffuse easily across biological membranes
Many off target/non-target effects
Immunoglobulin as drugs:
antibodies used as drugs belong to immunoglobulin G (igG) class
IgG accounts for 75-80% of naturally occurring antibodies
Second most common protein in plasma (5-13 g/L)’ albumin 35-50 g/L
Structure of IgG
Two heavy chains
Two light chains
Connected by disulfide bonds
Variable region provides the specificity
Variable region contains CDR (complementarity-determining region; not shown here)
Variable recognize antigen – specificity
FAB and Fc
Fraction of antigen binding : Most important region for recognizing antigen
Fraction of crystallizable
IgG action and structure
When it binds to its target through Fab region, it can bring in different cells (NK, etc. -**Relisten
Can also bring in different complement to initiate CDC (Complement dependent cytotoxicity)
FC region is important in initiating activation of immune cells
Fc Receptor types
FcyR
FcRn (neonatal FcR)
FC receptors: FcyR
Crystallized structure
Y shape
L, light, H, heavy, V variable
IMPORTANT: FC region
Contains binding site for Fc receptor expressed on immune cells: Fcy receptor
Also binds to C1Q
Responsible for binding to certain immune cells for cytotoxicity - relisten
Involved in mediating immune responses
Expressed on immune cells
FC receptors: FCRN
Different FC receptor: FcRN
FC
R = receptor
N = neonatal
Expressed on endothelial cells and immune cells
Involved in uptake into cells
mAb function
Targets of mAb are either on the cell membrane or circulating in the blood
mAb function: targeting on cell membrane:
MAB binding to protein called HER2
HER2 – protein expressed on cell membrane
Expressed on breast
Give MAB to a breast cancer patient, bind to HER2, get internalized, and lead to lysosomal degradation = decreased HER expression
OR antibody undergoes antibody dependent cytotoxicity – brings in different immune cells
mAb function: Circulating target
TNF-a
Cytokine mediating inflammation
Once it binds to target – initiates binding that leads to inflammation
Infliximab
Binds to TNFa – falls into it
Decreased level of TNF-a that binds with target = decreased inflammation
mAb: Absorption
Cannot be taken orally due to instability in GI tract and difficult in permeating the intestinal epithelium
Must be given parenterally (e.g. IV, SC, or IM)
Reach systemic circulation by **convective flow of the interstitial fluids into lymphatic capillaries into lymphatic channels **
CANNOT give orally – body will be treated as big protein, used as nutrient source
Out of three methods: subq is preferred because patient can administer themselves
Lymphatic system
One-way transport system for fluid and proteins by collecting them from interstitial space returning them to blood circulation
Lymph flow rate is 100-500 times slower than that of blood
The protein composition of lymph is nearly equivalent to that of interstitial fluid
Serves as a major transport route for immune cells and macromolecules
mAB absorption process
Put drug into interstitial space
Small molecule drug as subq – typically go through lipid bilayer – small, can cross by passive diffusion
Typical route for small molecule absorption
Pass through capillary membrane
Mabs are too thick, cannot go through membrane
Lymphatic system explained
Relatively high blood pressure
Because of that – some liquids squeeze through blood membranes and reach interstitial fluid area
Fluid accumulation – bad
Lymphatic – collects accumulated fluid back to the blood system
Takes care of extra fluid in interstitial space
Flow happens due to differences in pressure = Convective flow (fluid moving down the gradient)
Major pathway for mAb
Convective flow of the interstitial fluid into lymphatic channel
Minor pathway for mAbs
Diffusion through interstitial fluid and transport across blood capilary
(for small proteins (<5kD size)
Vd of mAb range
lies between that of plasma (0.04L/Kg) and extracellular water (0.23 L/kg)
-mAbs too big to cross - stuck in blood and plasma
mAb disposition:
Bioavailability – not 100%
There are _ to take care of Mabs when you inject
Relatively low at injection site: proteolysis at injection site
RESULT: Small protein and _ = become nutrients
Peak time: 3days – 1 week
Much slower time
Only relevant to IM and subq – IV fast
Half life – unit of days, weeks, or sometimes months
Antibodys hang in body for pretty long time due to FCrn recycling
revisit table
FcRn (neonatal Fc receptor)
Originally identified as a receptor for transporting maternal IgG to neonates via maternal milk
Expressed in many tissues including placenta syncytiotrophoblast and vascular endothelium
Serves as trasnport mechanism for IgG from maternal to fetal
IgG salvage by FcRn
The endothelial cells internalize serum IgG which binds to FcRn in an acidic endosomal compartment. FcRn then recycles IgG back into circulation, extending its serum half-life
FcRn in endothelial cells protects IgG from catabolism
