Disposition of metabolically radiolabeled CE9.1--a macaque-human chimeric anti-human CD4 monoclonal antibody--in transgenic mice bearing human CD4.
IDEC-CE9.1 is a macaque/human chimeric IgG1 monoclonal antibody (mAb) directed against the human T-lymphocyte receptor, CD4. CE9.1 is highly specific for the human receptor and is known to cross-react only with chimpanzee CD4. Thus, limited in vivo investigations have been performed that would be expected to reflect the behavior of this mAb in humans. CE9.1 was metabolically radiolabeled using [3H]leucine, and studies of the distribution and pharmacokinetics of [3H]CE9.1 were performed in transgenic mice bearing either the hCD4 receptor in place of the mouse receptor (CD4+), or no CD4 receptor (CD4-). Single-dose studies were performed after intravenous administration of approximately 0.4 and 100 mg/kg. The disposition of CE9.1 was highly dependent on the presence and distribution of the hCD4 receptor. After a low intravenous dose to CD4+ mice, rapid loss of [3H]CE9.1 from plasma (mean residence time < 1 hr) was accompanied by accumulation of radioactivity in the spleen (a maximum of 18% of the administered dose at 2 hr). By contrast, no significant uptake of radiolabel was observed in the spleen of CD4- mice after a low intravenous dose (< 1%), and plasma radioactivity exceeded 40% of the administered dose at 24 hr. Significant accumulation of radiolabel was observed in the liver of both CD4+ and CD4- mice (maximum of 9-13%), suggesting this process was not CD4-receptor-mediated. After a high intravenous dose to CD4+ mice, the mean residence time of CE9.1 was approximately 24 hr, and dose-normalized plasma area under the concentration vs. time curve was within a factor of 2 of that observed in CD4- mice. Spleen radioactivity was < 1% after a high intravenous dose to CD4+ mice, whereas in the liver, the profile of radioactivity was similar in CD4+ mice at 0.4 and 100 mg/kg.
Davis
C B
CB
Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
Garver
E M
EM
Kwok
D C
DC
Urbanski
J J
JJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007930:Leucine; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D014018:Tissue Distribution; D014316:Tritium
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D014316:Tritium; D007930:Leucine