Fc receptor non-binding anti-cd3 monoclonal antibodies deliver a partial tcr signal and induce clonal anergy

摘要

Anti-CD3 mAbs are potent immunosuppressive agents used in clinical transplantation. However, the activation-related adverse side effects associated with these mAbs have prompted the development of less toxic Fc receptor non-binding anti-CD3 mAb therapies. At present, the functional and biochemical consequences of T cell exposure to Fc receptor non-binding anti-CD3 is unclear. In this study, the inventors have examined the early signaling events triggered by a Fc receptor non-binding anti-CD3 mAb. Like the mitogenic anti-CD3 mAb, Fc receptor non-binding anti-CD3 triggered changes in the TCR complex, including zeta chain tyrosine phosphorylation and ZAP-70 association. However, unlike the mitogenic anti-CD3 stimulation, Fc receptor non-binding anti-CD3 was ineffective at inducing the highly phosphorylated form of zeta (p23) and tyrosine phosphorylation of the associated ZAP-70 tyrosine kinase. This proximal signaling deficiency correlated with minimal PLC gamma -1 phosphorylation and failure to mobilize detectable Ca2+. Not only did biochemical signals delivered by Fc receptor non-binding anti-CD3 resemble altered peptide ligand signaling, but exposure of Th1 clones to Fc receptor non-binding anti-CD3 also resulted in functional anergy. Finally, a bispecific anti-CD3 x anti-CD4 F(ab)'2 reconstituted early signal transduction events and induced proliferation, suggesting that defective association of 1ck with the TCR complex may underlie the observed signaling differences between the mitogenic and Fc receptor non-binding anti-CD3.