Use of hu-IgG-SCID mice to evaluate the in vivo stability of human monoclonal IgG antibodies.
Human and in vitro modified mAbs such as humanized rodent mAbs and immunotoxins are now considered for a variety of applications in humans. The adequate in vivo stability of these Ig preparations is not easily predicted from in vitro studies and may be essential for many therapeutic applications. In this study, we report the development and characterization of an in vivo model for testing this parameter using SCID mice containing a physiological concentration of human IgG (hu-IgG-SCID). The model was tested with several IgG1 and IgG3 human mAbs reacting with the human Rh(D) red cell antigen. It is known that human IgG have a shorter half-life in SCID mice than in humans. However, our results showed that the half-life of IgG3 mAbs (1.5 +/- 0.5 days) was much shorter than the one of IgG1 mAbs (5.8 +/- 1.4 days), indicating that the relative stability of IgG1 and IgG3 human mAbs in hu-IgG-SCID mice is similar to the one previously reported in humans (21 days vs. 7 days respectively). The IgG catabolism rate in humans is known to be inversely proportional to serum IgG concentrations. Accordingly, the dilution of the mAbs in a large excess (200-fold) of human IgG was found to be an important parameter of the hu-IgG-SCID mouse model since much longer (3-4-fold) mAb half-lives were obtained in the presence of a lower dose or in the absence of co-injected human IgG. This study show the usefulness of this animal model for the evaluation of human antibody stability in an in vivo environment.
Bazin
R
R
Canadian Red Cross, Blood Services, Quebec.
Boucher
G
G
Monier
G
G
Chevrier
M C
MC
Verrette
S
S
Broly
H
H
Lemieux
R
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism* / Q000627:therapeutic use; D000918:Antibody Specificity; D004355:Drug Stability; D000939:Epitopes; D005069:Evaluation Studies as Topic; D006801:Humans; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism* / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D012204:Rh-Hr Blood-Group System / Q000276:immunology
D000911:Antibodies, Monoclonal; D000939:Epitopes; D007074:Immunoglobulin G; D012204:Rh-Hr Blood-Group System; C026410:Rho(D) antigen