A. Sharma et al., Comparative pharmacodynamics of keliximab and clenoliximab in transgenic mice bearing human CD4, J PHARM EXP, 293(1), 2000, pp. 33-41
Citations number
23
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Keliximab and clenoliximab are monkey/human chimeric CD4 monoclonal antibod
ies (mAbs) of the IgG1 and IgG4 isotypes, respectively. The pharmacokinetic
s (PK) and pharmacodynamics (PD) of these mAbs were evaluated in transgenic
mice bearing human CD4 molecules on their T cells after a single i.v. admi
nistration at three dose levels (5-125 mg/kg). The PK of keliximab and clen
oliximab were similar, dose-dependent, and adequately described by a two-co
mpartment model with saturable elimination from both compartments, The enum
eration of circulating CD4(+) T cells and density of CD4 on their surface w
ere determined as the PD effects. An indirect response model was proposed t
o characterize the PD effects. With the increase in mAb dose, the maximum i
ntensity (R-max ) of PD effects was increased, and the time to reach R-max
shifted to later times. At all three dose levels, keliximab caused a relati
vely rapid decline in the number of circulating CD4(+) T cells, which then
recovered gradually. In contrast, clenoliximab at the lowest dose (5 mg/kg)
did not produce a significant effect on CD4(+) T cell counts compared with
the placebo group. At high doses, clenoliximab caused a significant decrea
se in the number of CD4(+) T cells. Keliximab appeared to be more potent an
d efficient in depleting CD4(+) T cells. Both mAbs produced similar down-mo
dulation of CD4 at corresponding dose levels. The findings of this study ar
e consistent with the results of a recent clinical trial that emphasize the
importance of this transgenic mouse model for evaluating PK/PD to support
clinical development of anti-human CD4 mAbs.