Biologics Flashcards
Biologics
-derived from living material
-complex structure
examples of biologics
-mAbs
-cytokines, GFs, enzymes
-therapeutic proteins
-vaccine
mAbs
-target specific
-side effects related to exagerated effects
-LARGE
small molecule drugs
-more prone to induce harmful non-target effects
Igs as drugs
-mostly IgGs
-2nd most common protein in plasma after albumin
Ig structure
-2 heavy chain
-2 light chain
-variable region (tips)
-constant region
-Fab
-Fc
IgG action
-phagocytosis by macrophages
-lysis by NK cell
-activate complement
Fc region
-interacts with Fc receptors leading to activation of immune system
FcyR
-expressed on immune cells
-involved in mediating immune responses
FcRn (neonatal FcR)
-expressed on endothelial cells, enterocytes, immune cells
-involved in IgG uptake into cells
mAb function
-targets are either on cell membrane or in blood
-targeting complex leads to defradation of complex and triggers ADCC
mAb admin
-cannot be taken orally bc GI tract and bad permeability
-must be given parenterally
parenterally
-SC
-IM
-IV
mAb absorption
-reaches systemic circulation by connective flow of intersitial fluids into lymphatic capillaries into lymphatic channels
Lymphatic system
-one way transport for fluid and proteins
-collect them in interstitial space and return them to blood circ
-100-500x slower than blood flow
-major transport route of immune cells and macromolecules
-protein comp of lymp is same as interstitial fluid
Major pathway of mAb absorption
-IM or SC shot into interstitial fluid
-taken up by lymph
-put into plasma
Minor pathway of mAb absorption
-diffusion through interstitial fluid and transport across blood capillary
-mostly small proteins tho
mAb distribution
-small volume of distribution
mAb disposition
-not 100% bioavailability
-lots of degradation by proteolysis while they wait on lymph node
mAb peak time
-days
-slow lymph absorption
-half life is also days bc FcRn
FcRn
-originally ID as receptor for transporting maternal IgG to neonate via milk
-expressed in many tissues in placenta to transport IgG to fetus also
IgG salvage by FcRn
-endothelial cells intenalize IgG
-IgG binds FcRn in an acidic endosomal compartment
-FcRn recycles IgG back to circulation
= inc half life
-FcRn protects IgG from catabolism
FcRn binding increases
IgG half life by delaying elimination
mAb elimination
-NO hepatic metabolism
-INSIGNIFICANT renal elimination
-mainly proteolytic degradation
-specific or nonspecific clearance pathway
Proteolytic degradation
-main elimination of mAbs
Nonspecific clearance pathway
-proteolysis by RES (immune cells)
-dose-INdependent
specific clearance pathway
-target-mediated
-binds to target and goes down with it
-dose DEPENDENT
other clearance pathway
-antidrug antibody-mediated clearance
Reticuloendothelial System
-mononuclear phagocyte system
-liver, bone marrow, lymph
-nonspecific uptake and catabolism
Kupffer’s cells
-sinusoidal capilaries (holes)
-slow but large capacity
-part of RES
Target-mediated clearance
-mAb binds to antigen
-might be internalized orcatabolized as antibody-antigen complex
-faster than clearance
-DOSE DEPENDENT (nonlinear)
-high doses saturate pathway
Elimination of high dose mAb
-slow
-RES bc target-mediated is saturated
-linear clearance (predictable)
Elimination of low dose mAb
-rapid
-RES + target-mediated
-nonlinear clearance (unpredictable)
Antidrug antibodies
-mAbs might trigger immune response (antidrug antibody ADA formation)
-inc fraction of nonhuman seq in protein molecule leads to more immune response
Immunogenecity
-ADA-mAb complex that is cleared by RES
-faster clearance
-SC admin more at risk
-length of treatment also more at risk
