American Diabetes Association
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A cell-surface autoantibody targets zinc transporter-8 (ZnT8) for in vivo B-cell imaging and islet-specific therapies

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posted on 2022-11-29, 19:44 authored by Zheng Guo, Devi Kasinathan, Chengfeng Merriman, Maki Nakayama, Hua Li, Huilin Li, Cheng Xu, G. William Wong, Liping Yu, Maria L. Golson, Dax Fu

Type 1 diabetes (T1D) is a disease in which autoimmune attack is directed to the insulin-producing b-cell in the pancreatic islet. Autoantigens on the b-cell surface membrane are specific markers for molecular recognition and targets for engagement by autoreactive B lymphocytes, which produce islet cell surface autoantibody (ICSA) upon activation. Here, we report the cloning of an ICSA (mAb43) that recognizes a major T1D autoantigen, ZnT8, with a subnanomolar binding affinity and conformation specificity. We demonstrate that cell-surface binding of mAb43 protects the extracellular epitope of ZnT8 against immunolabeling by serum ICSA from a patient with T1D. Further, mAb43 exhibits in vitro and ex vivo specificity for islet cells, mirroring the exquisite specificity of islet autoimmunity in T1D. Systemic administration of mAb43 yields a pancreas-specific biodistribution in mice and islet homing of a mAb43-linked imaging payload through the pancreatic vasculature, thereby validating the in vivo specificity of mAb43. Identifying ZnT8 as a major antigenic target of ICSA allows for research into the molecular recognition and engagement of autoreactive B cells in the chronic phase of T1D progression. The in vivo islet specificity of mAb43 could be further exploited to develop in vivo imaging and islet-specific immunotherapies.


This study was supported by the National Institutes of Health, R56 DK123435 (D.F), R01DK125746 (D.F), P30DK116073 (L.Y), R01DK110183 (M.L.G.), RO1DK084171 (G.W.W), and NIH R01 NS127292 (H. L). The authors thank Hao Zhang from the Flow Cytometry and Immunology Core Facility at Johns Hopkins Bloomberg School of Public Health for his assistance in flow cytometry data acquisition and analysis. The authors also thank Hoku West-Foyle from the Microscope Facility of Johns Hopkins University School of Medicine for his assistance in wholemount pancreas data acquisition and analysis. The Zeiss confocal microscope was funded through the National Institutes of Health shared instrumentation Grant S10OD016374. The MoFlo XDP cell sorter was funded through National Institutes of Health Grants S10OD016315 and S10RR13777001. This manuscript used data and tissue acquired from the Human Pancreas Analysis Program (HPAP-RRID:SCR_016202) Database (, a Human Islet Research Network (RRID:SCR_014393) consortium (UC4-DK-112217, U01-DK-123594, UC4-DK-112232, and U01-DK-123716).