Subcutaneous bioavailability of a PRIMATIZED IgG1 anti-human CD4 monoclonal antibody is dose dependent in transgenic mice bearing human CD4.
IDEC-CE9.1/SB-210396 is a macaque/human chimeric IgG1 monoclonal antibody (mAb) directed against the human T-cell surface marker, CD4. This antibody has been evaluated as a potential treatment for rheumatoid arthritis and asthma, in which T cell activation is believed to play an important role in orchestrating inflammation and tissue damage. Human CD4+ murine CD4 knock-out transgenic mice (HuCD4+) have proven most useful in studying the pharmacology of CE9.1, since this antibody cross-reacts only with chimpanzee CD4 and the disposition of the antibody is highly dependent on the presence and distribution of human CD4. In the present study, the distribution and pharmacokinetics of [(3)H]CE9.1 were investigated after subcutaneous (sc) administration to HuCD4+ and murine CD4 knock-out (CD4-) transgenic mice (doses of 0.4 and 100 mg/kg). After a low sc dose to HuCD4+ mice, no absorption of CE9.1 into the systemic circulation was observed. By contrast, high systemic exposure was noted following a comparable sc dose to CD4- mice. Based on evidence that absorption of large proteins occurs primarily via the lymphatics (Supersaxo et al., Pharm. Res. 7:167, 1990), it is proposed that specific binding of CE9.1 to the CD4 molecule on lymphocytes in the regional lymph node(s) prevented the mAb from entering the systemic circulation. Saturation of CD4 binding following a high sc dose to HuCD4+ mice resulted in systemic exposure comparable to that observed at lower doses in CD4- mice. Furthermore, absorption of a low sc dose of [(3)H]CE9.1 was increased 30-fold by administration 7 h earlier of a high sc dose of unlabeled CE 9.1.
Davis
C B
CB
Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA.
Bugelski
P J
PJ