Biologics PK handout

Question 1

Biologics

• generally derived from ___ material
• ___ in structure

Answer 1

• living
• complex

Question 2

Examples of biologics

Answer 2

• monoclonal antibodies
• cytokines
• growth factors
• enzymes
• immunodulators/immunotherapies
• proteins
• vaccines
• blood producrs
• gene therapy

Question 3

Monoclonal antibodies
* target specific
* their side-effects are mostly related to exaggerated ___ effects

Answer 3

pharmacological

Question 4

Small molecule drugs
* more prone to induce
___ effects

Answer 4

harmful non-target

Question 5

• Antibodies used as drugs belong to ___ class
• accounts for ___ of naturally occurring antibodies

Answer 5

• IgG
• 75-80%

Question 6

IgG action

• ADCP
• CDC
• ADCC

Answer 6

• antibody dependent cellular phagocytosis
• complement depenent cytotoxicity
• antibody dependent cellular cytotoxicity

Question 7

mAb: Absorption

• Cannot be taken ___ due to instability in GI tract and difficulty in permeating the intestinal epithelium
• Must be given ___
• Reach systemic circulation by ___ flow of the interstitial fluids into ___ capillaries into ___ channels

Answer 7

• orally
• parenterally
• convective, lymphatic

Question 8

major pathway for mAb: ___
minor pathway for mAb: ___

Answer 8

• convective
• diffusion

Question 9

Lymphatic system

• ___ transport system, for fluid and proteins by collecting them from ___ space and returning them to ___ circulation
• lymph flow rate is 100-500 times ___ than blood
• the protein composition of lymph is nearly equivalent to ___
• major transport route for ___ cells and macromolecules

Answer 9

• one way, interstitial, blood
• slower
• interstitial fluid
• immune

Question 10

Lymph drains into blood circulation
* right lymph duct → right ___ vein
* ___ duct → left subclavian veins

Answer 10

• subclavian
• thoracic

Question 11

mAb: Distribution

Volume of distribution of mAB lies between that of ___ (0.04 L/kg) and extracellular ___ (0.23 L/kg)

Answer 11

• plasma
• water

Question 12

mAb: Elimination

• Renal elimination of mAb is ___
• mAbs are mainly eliminated through ___, resulting in smaller peptides and amino acid
• Pinocytosis by endothelial cells involving ___ extends IgG ___ (IgG recycling)
• Clearance from circulation is via ___ or ___ pathway

Answer 12

• insignificant
• proteolytic degradation
• FcRn, half life
• nonspecific, specific

Question 13

Fc receptors

Answer 13

• FcγR
• FcRn (neonatal FcR)

Question 14

Nonspecific clearance pathway

Proteolysis by ___ (RES):
* Dose-___ as therapeutic mAb concentration is below endogenous ___ level (10 mg/ml)

Answer 14

• reticuloendothelial system
• independent, IgG

Question 15

Specific clearance pathway

Target-mediated clearance
* Dose-___ as antibody binding to the target antigen can be ___

Answer 15

• dependent
• saturated

Question 16

mAb elimination: IgG salvage by FcRn

• ___ Fc receptor
• expressed in ___ syncytiotrophoblast and
  ___ endothelium
• FcRn in endothelial cells protects ___ from catabolism
• The cells internalize IgG which binds to ___ in an acidic endosomal
  compartment. FcRn then recycles IgG back into circulation, extending its serum ___

Answer 16

• neonatal
• placenta and vascular
• IgG
• FcRn, half life

Question 17

T or F: The absence of FcRn leads to faster mAb elimination

Answer 17

true

Question 18

FcRn binding delays mAb ___
and extends mAb half-life

Answer 18

elimination

Question 19

mAb elimination: Reticuloendothelial system (RES)

• ___ phagocyte system
• part of the ___ that consists of the phagocytic cells located in reticular connective tissue (liver, bone marrow, and lymphoid)
• immune cells binding to ___ region of antibody, followed by receptor-mediated endocytosis and degradation in lysosome

Answer 19

• mononuclear
• immune system
• Fc

Question 20

Specific clearance pathway: Target mediated disposition

• After mAbs bind to a specific antigen, they may be ___ or ___
• Most prominent for ___ antigen
• at high doses of mAb, pathway is ___

Answer 20

• internalized or catabolized
• membrane bound
• saturated

Question 21

mAb: Immunogenecity

• mAbs may trigger an immune response, formation of ___ (ADA), in patients
• increased fraction of ___ sequence in the protein molecule leads to more immune response.

Answer 21

• antidrug antibodies
• nonhuman

Question 22

mAb: Immunogenecity

• Both ___and ___ ADA form circulating ADA-mAb immune complex that is cleared by ___
• ___ route has higher likelihood for ___ at the injection site
• as duration of treatment lengthens, the chances to elicit an immune response ___
• ADA-mAb complex formation may increase mAb ___

Answer 22

• neutralizing, non-neutralizing, RES
• aggregate formation
• increases
• clearance

Question 23

Answer 23

Question 24

T or F: Cytochrome P450 enzymes in the liver play critical roles in elimination of
monoclonal antibodies

Answer 24

False

Question 25

T or F: Oral route is the preferred route of administering biologics

Answer 25

False

Question 26

T or F: Genetic engineering of Fc portion of mAb for better binding affinity to FcRn is expected to increase mAb half-life

Answer 26

True

Question 27

T or F: Ranibizumab is Fab fragment of antibody targeting VEGF (vascular endothelial growth factor) while bevacizumab is a full-sized antibody. Clearance of ranibizumab is expected to be faster than that of bevacizumab.

Answer 27

True

Question 28

T or F: After months of infliximab (mAb against TNFa) treatment for a patient with inflammatory bowel disease, anti-infliximab antibodies are detected. The elimination rate of infliximab is expected to increase as compared to the beginning of therapy.

Answer 28

True

Question 29

T or F: Antidrug antibodies (ADA) against mAb typically increase both the elimination rate and the efficacy of mAb.

Answer 29

False

Question 30

T or F: mAb engineering for increased binding to FcRn can increase the mAb half-life

Answer 30

True

Question 31

T or F: mAb engineering for enhanced binding to FcγR can improve potency

Answer 31

True