La. Chau et al., HuM291 (NUVION), a humanized Fc receptor-nonbinding antibody against CD3, anergizes peripheral blood T cells as partial agonist of the T cell receptor, TRANSPLANT, 71(7), 2001, pp. 941-950
Background. Humanized Fc receptor (FcR)-nonbinding antibodies against CD3 a
re promising immunosuppressive agents that may overcome both the neutralizi
ng response to and the cytokine release syndrome seen with conventional mon
oclonal antibodies against CD3, In addition, evidence from several murine m
odels suggests that these recombinant antibodies may actively induce T cell
unresponsiveness by a mechanism other than modulation of the T cell recept
or (TCR) or T cell depletion. We hypothesized that FcR-nonbinding antibodie
s against CD3 could induce T cell unresponsiveness by acting as partial ago
nist ligands of the TCR and thus, inducing T cell anergy,
Methods. To test this hypothesis, we examined the signaling and functional
effects of HuM291 (Nuvion(TM)), a FcR-nonbinding humanized antibody against
CD3, on primary human T cells.
Results. Short exposure of human peripheral blood T lymphocytes to HuM291 c
aused a partial agonist type of signaling through the TCR characterized by
incomplete phosphorylation of TCR zeta, failure to activate ZAP-70 and to p
hosphorylate LAT but activation of ERK-1/-2 and subsequent up-regulation of
CD69 expression. These changes correlated with a dose-dependent induction
of anergy in human, primary resting T cells, which was reversed by exogenou
s interleukin-2.
Conclusions. The tolerogenic properties of FcR-nonbinding monoclonal antibo
dies against CD3 correlate with its ability to reproduce the biochemical an
d functional effects of TCR partial agonist ligands, Thus, generation of en
gineered antibodies against CD3 with low TCR oligomerization potential may
provide a clinically applicable partial agonist-based strategy for the prev
ention of polyclonal T cell responses.