PHRM 835 Exam 2 Biologics

Question 1

biologics are generally derived from ?

Answer 1

living material

Question 2

IgG accounts for what percent of naturally occurring antibodies?

Answer 2

75-80%

Question 3

two Fc receptors to know

Answer 3

Fcyr (Fc gamma R)
FcRn (neonatal FcR)

Question 4

targets of monoclonal antibodies are found where? (2 places)

Answer 4

-on cell membrane (ex. Herceptin)
-circulating in the blood (ex. infliximab; TNFa antibody)

Question 5

mAb’s cannot be taken through which route?

Answer 5

orally

Question 6

mAb major absorption pathway

Answer 6

by convective flow of the interstitial fluid into lymphatic capillaries into lymphatic channels

Question 7

mAb minor absorption pathway

Answer 7

diffusion through interstitial fluid and transport across blood capillary

Question 8

the mAb minor absorption pathway is for

a. small proteins
b. big proteins

Answer 8

a. small proteins

(< 5 kD size)

Question 9

which is faster, blood flow rate or lymph flow rate?

Answer 9

blood flow rate

(lymph flow rate is 100-500 times slower)

Question 10

where does lymph drain into?

Answer 10

blood circulation (systemic)

Question 11

mAbs are mainly eliminated through _____ _____

Answer 11

proteolytic degradation

Question 12

what process extends IgG half-life?

Answer 12

pinocytosis by endothelial cells involving FcRn (IgG recycling)

Question 13

two mAb clearance pathways

Answer 13

nonspecific and specific clearance pathways

Question 14

what is the nonspecific clearance pathway for mAbs?

Answer 14

proteolysis by reticuloendothelial system (RES)

Question 15

what is the specific clearance pathway for mAbs?

Answer 15

target mediated disposition (elim. of mAbs through its antigen-specific interactions)

Question 16

the nonspecific clearance pathway is

a. dose-independent
b. dose-dependent

Answer 16

a. dose-independent

(therapeutic mAb concentration is below endogenous IgG level 10 mg/mL)

Question 17

the specific clearance pathway is

a. dose-independent
b. dose-dependent

Answer 17

b. dose-dependent

(antibody binding to the target antigen can be saturated)

Question 18

how does the reticuloendothelial system work?

Answer 18

immune cells bind to Fc region of antibody -> receptor-mediated endocytosis -> degradation in lysosome

Question 19

example of drug in class that uses specific clearance pathway

Answer 19

Efalizumab

Question 20

what is Efalizumab used to treat?

Answer 20

psoriasis

Question 21

high dose Efalizumab has ___ elimination

a. rapid
b. slow

Answer 21

b. slow

Question 22

low dose Efalizumab has ___ elimination

a. rapid
b. slow

Answer 22

a. rapid

Question 23

mAB immunogenecity: what does it means?

Answer 23

increased fraction of nonhuman sequence in the molecule leads to more immune response

(mouse <- chimeric <- humanized <- human)

Question 24

which has the most immunogenecity?

a. abciximab
b. adalimumab
c. muromonab
d. daclizumab

Answer 24

c. muromonab

Question 25

absorption of mAbs is mainly through _____ uptake due to their large molecular size

Answer 25

lymphatic

Question 26

true or false: Cytochrome P450 enzymes in the liver play critical roles in elimination of monoclonal antibodies

Answer 26

false

Question 27

true or false: Oral route is the preferred route of administering biologics

Answer 27

false

Question 28

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

Answer 28

true

Question 29

true or false: 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 shorter than that of bevacizumab

Answer 29

true (no Fc so doesn't bind to FcRn -> antibody elim will be really fast)

Question 30

True or false: 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 30

true

Question 31

true or false: Antidrug antibodies (ADA) against mAb typically increase both the elimination rate and the efficacy of mAb

Answer 31

false (it does increase elim rate but efficacy will decrease)

Question 32

true or false: mAb engineering for increased binding to FcRn can increase the mAb half-life

Answer 32

true (M252Y/S254T/T256E mutations on motavizumab led to a 10-fold increase in FcRn affinity and significantly increased its half-life)

Question 33

true or false: mAb engineering for enhanced binding to FcyR (Fc gamma R) can improve potency

Answer 33

true (Anti-CD20 antibody, obinutuzumab and ocrelizumab, show enhanced FcgR binding affinity and greater potency compared to a first-generation antibody, rituximab)