The use of severe combined immunodeficiency mice to study the metabolism of human immunoglobulin G.
BACKGROUND
Although the four human immunoglobulin G (IgG) isotypes are similar in structure, they exhibit significant differences in effector function and catabolic half-life. With advent of structurally engineered antibodies, there is the potential to design antibody constructs with desired half-lives; however, it is first necessary to discover the structures and mechanisms that control immunoglobulin metabolism.


METHODS
Radioiodinated chimeric antibodies, consisting of a mouse antidansyl variable region and the four human IgG constant regions, were injected intravenously into Balb/c and severe combined immunodeficiency (SCID) mice, and their half-lives were determined by whole body and whole blood counting. Dependence of the rate of immunoglobulin catabolism on immunoglobulin concentration, a normal regulatory phenomenon specific to IgG, was evaluated by the introduction of large amounts of human gamma-globulin intraperitoneally.


RESULTS
Whole body and blood half-lives were statistically indistinguishable. The four IgG isotypes were eliminated from the whole animals in a predominantly single-phasic manner, with the half-life being dependent on the isotype studied. In Balb/c mice, immune elimination frequently occurred after 6 days, although this was not observed in SCID mice. Relevance of the model was confirmed by the demonstration of the presence of the concentration-catabolism phenomenon, a relationship unique to normal IgG regulation.


CONCLUSIONS
SCID mice provide an adequate initial animal model for the study of human-mouse chimeric antibodies. Further understanding of the factors governing immunoglobulin catabolism can be probed by study of recombinant human constant regions in this animal system.
Zuckier
L S
LS
Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, NY 10461.
Georgescu
L
L
Chang
C J
CJ
Scharff
M D
MD
Morrison
S L
SL
D000818:Animals; D006207:Half-Life; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D007132:Immunoglobulin Isotypes / Q000378:metabolism; D007457:Iodine Radioisotopes; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D011993:Recombinant Fusion Proteins
D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D007457:Iodine Radioisotopes; D011993:Recombinant Fusion Proteins