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Kinetics > Biologics > Flashcards

Biologics Flashcards

1
Q

Biologics

A

-derived from living material
-complex structure

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2
Q

examples of biologics

A

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

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3
Q

mAbs

A

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

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4
Q

small molecule drugs

A

-more prone to induce harmful non-target effects

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5
Q

Igs as drugs

A

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

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6
Q

Ig structure

A

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

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7
Q

IgG action

A

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

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8
Q

Fc region

A

-interacts with Fc receptors leading to activation of immune system

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9
Q

FcyR

A

-expressed on immune cells
-involved in mediating immune responses

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10
Q

FcRn (neonatal FcR)

A

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

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11
Q

mAb function

A

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

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12
Q

mAb admin

A

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

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13
Q

parenterally

A

-SC
-IM
-IV

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14
Q

mAb absorption

A

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

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15
Q

Lymphatic system

A

-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

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16
Q

Major pathway of mAb absorption

A

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

17
Q

Minor pathway of mAb absorption

A

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

18
Q

mAb distribution

A

-small volume of distribution

19
Q

mAb disposition

A

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

20
Q

mAb peak time

A

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

21
Q

FcRn

A

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

22
Q

IgG salvage by FcRn

A

-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

23
Q

FcRn binding increases

A

IgG half life by delaying elimination

24
Q

mAb elimination

A

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

25
Q

Proteolytic degradation

A

-main elimination of mAbs

26
Q

Nonspecific clearance pathway

A

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

27
Q

specific clearance pathway

A

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

28
Q

other clearance pathway

A

-antidrug antibody-mediated clearance

29
Q

Reticuloendothelial System

A

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

30
Q

Kupffer’s cells

A

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

31
Q

Target-mediated clearance

A

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

32
Q

Elimination of high dose mAb

A

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

33
Q

Elimination of low dose mAb

A

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

34
Q

Antidrug antibodies

A

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

35
Q

Immunogenecity

A

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

36
Q
A

Kinetics (22 decks)

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