Dax Fu
725 N. Wolfe Street
Hunterian 401A
Baltimore MD 21205
Antigen-specific and islet-targeted immunotherapies for type-1 diabetes
Cell-surface autoantigens of pancreatic beta-cells are molecular attractants for autoreactive immune cells and thus therapeutic entry points to protect beta-cells from autoimmune attack that results in type-1 diabetes (T1D). Zinc transporter-8 (ZnT8) is a major cell-surface autoantigen expressed exclusively in the pancreatic islet. Our research program is built on a collection of ZnT8 monoclonal antibodies to develop antigen-specific and islet-targeted immunotherapies. We aim to achieve permanent protection or reversal of T1D using combination therapies that: (1) mask beta-cells from autoimmune recognition, (2) block islet-homing of autoimmune cells, (3) preserve autoimmune checkpoints, (4) promote beta-cell regeneration. We are developing mAb drugs in different therapeutic modalities inducing antibody-conjugated small molecules, biologics, lipid nanoparticles and engineered immune cells. The safety and efficacy of these therapeutics are tested in animal models. The mechanism of actions is investigated at the molecular and single-cell level to uncover the tipping points of immunological balance between immunity and autoimmunity.
Guo, Z., Kasinathan, D., Merriman, C., Nakayama, M., Li, H., Li, H., Xu, C., Wong, G. W., Yu, L., Golson, M. L., and Fu, D. (2022) A Cell-Surface Autoantibody Targets Zinc Transporter-8 (ZnT8) for in vivo beta-Cell Imaging and Islet-Specific Therapies. Diabetes. db220477. Online ahead of print.
Gu, Y., Merriman, C., Guo, Z., Jia, X., Wenzlau, J., Li, H., Li, H., Rewers, M., Yu, L., and Fu, D. (2021) Novel autoantibodies to the beta-cell surface epitopes of ZnT8 in patients progressing to type-1 diabetes. J Autoimmun 122, 102677
Merriman, C., Huang, Q., Gu, W., Yu, L., and Fu, D. (2018) A subclass of serum anti-ZnT8 antibodies directed to the surface of live pancreatic beta-cells. J Biol Chem 293, 579-587
Merriman, C., Li, H., Li, H., and Fu, D. (2018) Highly specific monoclonal antibodies for allosteric inhibition and immunodetection of the human pancreatic zinc transporter ZnT8. J Biol Chem 293, 16206-16216
Wan, H., Merriman, C., Atkinson, M. A., Wasserfall, C. H., McGrail, K. M., Liang, Y., Fu, D., and Dai, H. (2017) Proteoliposome-based full-length ZnT8 self-antigen for type 1 diabetes diagnosis on a plasmonic platform. Proc Natl Acad Sci U S A 114, 10196-10201
Huang, Q., Merriman, C., Zhang, H., and Fu, D. (2017) Coupling of Insulin Secretion and Display of a Granule-resident Zinc Transporter ZnT8 on the Surface of Pancreatic Beta Cells. J Biol Chem 292, 4034-4043
Merriman, C., Huang, Q., Rutter, G. A., and Fu, D. (2016) Lipid-tuned Zinc Transport Activity of Human ZnT8 Protein Correlates with Risk for Type-2 Diabetes. J Biol Chem 291, 26950-26957
Gupta, S, Chai, J., Cheng, J, D’Mello, R, Chance, MC, and Fu, D. Visualizing the kinetic power stroke that drives proton-coupled Zn(II) transport. Nature(2014)
Hoch E, Lin W, Chai J, Hershfinkel M, Fu D, Sekler I. Histidine pairing at the metal transport site of mammalian ZnT transporter controls Zn2+ over Cd2+ selectivity. Proc Natl Acad Sci U.S.A.,109(19):7202-7207 (2012).
Lin W, Chai J, Love J and Fu D. Selective electrodiffusion of zinc ions in a Zrt-, Irt-like protein, ZIPB. J Biol Chem., 285(50):39013-20 (2010).
Lu M, Chai J and Fu D. Structural basis for autoregulation of the zinc transporter YiiP. Nat. Struct. Mol. Biol., 16(10):1063-1067 (2009).
Lu M and Fu D. Structure of the zinc transport YiiP. Science, 317:1746-8 (2007). PubMed Full Text See also:Science Perspective by DH Nies: Science 317:1695-1696 (2007).
Fu D and Lu M. The structural basis of water permeation and proton exclusion in aquaporins (Review). Mol Membr Biol., 24(5):366-374 (2007).
Wei Y and Fu D. Binding and transport of metal ions at the dimer interface of the Escherichia coli metal transporter YiiP. J Biol Chem., 281(33):23492-23502 (2006).
Jiang J, Daniels BV and Fu D. Crystal structure of AqpZ tetramer reveals two distinct Arg-189 conformations associated with water permeation through the narrowest constriction of the water-conducting channel. J Biol Chem., 281(1):454-460 (2006).
Wei Y and Fu D. Selective metal binding to a membrane-embedded aspartate in the Escherichia coli metal transporter YiiP (FieF). J Biol Chem., 280(40):33716-33724 (2005).
Wei Y, Li H and Fu D. Oligomeric state of the Escherichia coli metal transporter YiiP. J Biol Chem., 279(38):39251-39259 (2004).
Chao Y and Fu D. Thermodynamic studies of the mechanism of metal binding to the Escherichia coli zinc transporter YiiP. J Biol Chem., 279(17):17173-17180(2004).
Chao Y and Fu D. Kinetic study of the antiport mechanism of an Escherichia coli zinc transporter, ZitB. J Biol Chem., 279(13):12043-12050 (2004).
Fu D, Libson A, Miercke LJ, Weitzman C, Nollert P, Krucinski J and Stroud RM Structure of a glycerol-conducting channel and the basis for its selectivity. Science, 290:481-486 (2000).