Yunxiang Zhu has completed his Ph.D. in Cell Biology at University of Miami School of Medicine in 2006 and fi nished his post-doctoral training in Dr. Stuart Kornfeld’s lab at University of Washington School of Medicine in St. Louis from 1996 to 2001. Currently, he is a distinguished fellow at Genzyme, a Sanofi company, working on drug discovery research for rare genetic diseases and autoimmune diseases. He has published more than 20 papers in reputed journals, including Science and PNAS.
Crosslinking of ligand-engaged cytotoxic T lymphocyte antigen-4 (CTLA-4) to the T cell receptor (TCR) during the early phase of T cell activation attenuates TCR signaling, leading to T cell inhibition. To promote this event, a bispecific fusion protein comprising a mutant mouse CD80 (CD80w88a) and lymphocyte activation antigen-3 was engineered to concurrently engage CTLA-4 and crosslink it to the TCR. Crosslinking is expected to be attained via ligation of CTLA-4 first to MHCII and then indirectly to the TCR, generating a CTLA-4-MHCII-TCR tri-molecular complex that forms between T cells and antigenpresenting cells during T cell activation. Treating T cells with this bispecific fusion protein in vitro inhibited T cell activation, induced production of IL-10 and TGF-, and attenuated AKT and mTOR signaling. Intriguingly, the bispecifi c fusion protein also directed early T cell diff erentiation into Foxp3 positive regulatory T cells (Tregs) in a process that was dependent on the endogenous production of TGF-. Treatment of non-obese diabetic (NOD) female mice between 4-13 weeks of age with the bispecifi c protein signifi cantly delayed the onset of disease or protected animals from developing autoimmune diabetes. Th us, bispecifi c fusion proteins that engage CTLA-4 and co-ligate it to the TCR during the early phase of T cell activation can negatively regulate the T cell response at multiple levels. Bispecifi c biologics with such dual functions may therefore represent a novel class of therapeutics for immune modulation. Th ese fi ndings presented here also reveal a potential new role for CTLA-4 in Treg diff erentiation.