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 imm unotoxins 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 therapeu tic applications. In this study, we report the development and charact erization of an in vivo model for testing this parameter using SCID mi ce 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 sh orter than the one of IgG1 mAbs (5.8 +/- 1.4 days), indicating that th e relative stability of IgG1 and IgG3 human mAbs in hu-IgG-SCID mice i s similar to the one previously reported in humans (21 days vs. 7 days respectively). The IgG catabolism rate in humans is known to be inver sely proportional to serum IgG concentrations. Accordingly, the diluti on 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 lo nger (3-4-fold) mAb half-lives were obtained in the presence of a lowe r 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.