therapeutic Abs

Question 1

structure and function of antibodies

Answer 1

four peptide chains, 2 heavy chains, 2 light chains

Fab region: Ag binding region , variable regions

Fc region: constant region of heavy chains, immune effector region that binds the Fc receptor

many FcRs (FcRn, FcRy)

function: recognize and binds specific sites on Antigens (epitopes) antigens are typically soluble proteins or cell surface proteins, induces immune response

Question 2

Types of Abs

Answer 2

immunoglobulins, IgM E A D G
IgG 1 2 3 and 4 differ in the Fc region

all therapeutic antibodies are IgG!

Question 3

therapeutic monoclonal Ab production and characteristics

Answer 3

can be mouse, human or transgenic

characteristics of therapeutic Abs:
homogenous for Ab type, AA sequence, affinity and specificity; high specificity, high affinity, long half life

murine- momab (completely mouse)
chimeric- ximab (partially mouse- most of the Fab)
humanized- zumab (almost all human )
human- umab (all human)

Question 4

administration and absorption of IgG

Answer 4

IV- 100% F
SubQ/ IM- 24-95% bioavailability, 7-8 days, absorbed slowly by connective absorption thru lymph

does not cross BBB

Question 5

neonatal FcRn for IgG

Answer 5

function: transfers passive immunity across placenta from mother to fetus, protects IgG from degredation prolonging half life in serum

expression in hepatocytes, endothelial cells, phago cytic cells and APCs
mechanism- binds the Fc region at acidic pH but not at physiological pH, IgG undergoes endocytosis into acidic pH endosomes and IgG binds FcRn
FcRn-IgG complex is resistant to lysosomal degredation (free IgG is degegraded)
FcRn-IgG is returned to cell surface at pH 7.4, and the IgG dissociates from FcRn
Recycles endocytosed IgG to cell surface-90% recylced
Ab fragments such as Fab lack Fc region and do not bind to FcRn

Question 6

half life of IgG

Answer 6

varies with IgG isotype (1 2 4 is 20-21 days) and (3 is 7 days)
differences due to catabolic protection by the neonatal Fc receptor bc IgG3 does not bind to FcRn

human mAb has a longer half life than murine bc the murine Ab does not bind to
antibody fragments- lack Fc region so dont bind to FcRn

Question 7

metabolism and elimination

Answer 7

presystemic catabolism by proteolysis in plasma, or at site of injection. Renal elimination unimportant bc of size, secretion of bile eliminates IgA only,

Question 8

mechanism of Action of therapeutic Abs

Answer 8

binding of Ab at specific site on Fab region of antigen (epitope)
Abs target soluble Anitgens/cell surface proteins

Can become antagonism or neutralization
cell signaling inhibition
antibody dependent cell cytotoxicity (ADCC)- induces lysis of a cell by a NK cell, neutrophil, macrophage
Complement dependent cytotoxicity

Question 9

side effects of Abs

Answer 9

generally safe and well tolerated, specific toxicity is related to MOA

immunogenicity: endogenous Abs against therapeutic Ab

murine has a higher immunogenicity than human