Biologics

Question 1

Biologics

Answer 1

-derived from living material
-complex structure

Question 2

examples of biologics

Answer 2

-mAbs
-cytokines, GFs, enzymes
-therapeutic proteins
-vaccine

Question 3

mAbs

Answer 3

-target specific
-side effects related to exagerated effects
-LARGE

Question 4

small molecule drugs

Answer 4

-more prone to induce harmful non-target effects

Question 5

Igs as drugs

Answer 5

-mostly IgGs
-2nd most common protein in plasma after albumin

Question 6

Ig structure

Answer 6

-2 heavy chain
-2 light chain
-variable region (tips)
-constant region
-Fab
-Fc

Question 7

IgG action

Answer 7

-phagocytosis by macrophages
-lysis by NK cell
-activate complement

Question 8

Fc region

Answer 8

-interacts with Fc receptors leading to activation of immune system

Question 9

FcyR

Answer 9

-expressed on immune cells
-involved in mediating immune responses

Question 10

FcRn (neonatal FcR)

Answer 10

-expressed on endothelial cells, enterocytes, immune cells
-involved in IgG uptake into cells

Question 11

mAb function

Answer 11

-targets are either on cell membrane or in blood
-targeting complex leads to defradation of complex and triggers ADCC

Question 12

mAb admin

Answer 12

-cannot be taken orally bc GI tract and bad permeability
-must be given parenterally

Question 13

parenterally

Answer 13

-SC
-IM
-IV

Question 14

mAb absorption

Answer 14

-reaches systemic circulation by connective flow of intersitial fluids into lymphatic capillaries into lymphatic channels

Question 15

Lymphatic system

Answer 15

-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

Question 16

Major pathway of mAb absorption

Answer 16

-IM or SC shot into interstitial fluid
-taken up by lymph
-put into plasma

Question 17

Minor pathway of mAb absorption

Answer 17

-diffusion through interstitial fluid and transport across blood capillary
-mostly small proteins tho

Question 18

mAb distribution

Answer 18

-small volume of distribution

Question 19

mAb disposition

Answer 19

-not 100% bioavailability
-lots of degradation by proteolysis while they wait on lymph node

Question 20

mAb peak time

Answer 20

-days
-slow lymph absorption
-half life is also days bc FcRn

Question 21

FcRn

Answer 21

-originally ID as receptor for transporting maternal IgG to neonate via milk
-expressed in many tissues in placenta to transport IgG to fetus also

Question 22

IgG salvage by FcRn

Answer 22

-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

Question 23

FcRn binding increases

Answer 23

IgG half life by delaying elimination

Question 24

mAb elimination

Answer 24

-NO hepatic metabolism
-INSIGNIFICANT renal elimination
-mainly proteolytic degradation
-specific or nonspecific clearance pathway

Question 25

Proteolytic degradation

Answer 25

-main elimination of mAbs

Question 26

Nonspecific clearance pathway

Answer 26

-proteolysis by RES (immune cells) -dose-INdependent

Question 27

specific clearance pathway

Answer 27

-target-mediated -binds to target and goes down with it -dose DEPENDENT

Question 28

other clearance pathway

Answer 28

-antidrug antibody-mediated clearance

Question 29

Reticuloendothelial System

Answer 29

-mononuclear phagocyte system -liver, bone marrow, lymph -nonspecific uptake and catabolism

Question 30

Kupffer's cells

Answer 30

-sinusoidal capilaries (holes) -slow but large capacity -part of RES

Question 31

Target-mediated clearance

Answer 31

-mAb binds to antigen -might be internalized orcatabolized as antibody-antigen complex -faster than clearance -DOSE DEPENDENT (nonlinear) -high doses saturate pathway

Question 32

Elimination of high dose mAb

Answer 32

-slow -RES bc target-mediated is saturated -linear clearance (predictable)

Question 33

Elimination of low dose mAb

Answer 33

-rapid -RES + target-mediated -nonlinear clearance (unpredictable)

Question 34

Antidrug antibodies

Answer 34

-mAbs might trigger immune response (antidrug antibody ADA formation) -inc fraction of nonhuman seq in protein molecule leads to more immune response

Question 35

Immunogenecity

Answer 35

-ADA-mAb complex that is cleared by RES -faster clearance -SC admin more at risk -length of treatment also more at risk