@article{b585802873834c3092e17d009ecefc76,
title = "Cell-Surface Autoantibody Targets Zinc Transporter-8 (ZnT8) for In Vivo β-Cell Imaging and Islet-Specific Therapies",
abstract = "Type 1 diabetes (T1D) is a disease in which autoimmune attacks are directed at the insulin-producing β-cell in the pancreatic islet. Autoantigens on the β-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. 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. Furthermore, 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 an 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.",
author = "Zheng Guo and Devi Kasinathan and Chengfeng Merriman and Maki Nakayama and Hua Li and Huilin Li and Cheng Xu and Wong, {G. William} and Liping Yu and Golson, {Maria L.} and Dax Fu",
note = "Funding Information: Acknowledgments. The authors thank Hao Zhang from the Flow Cytometry and Immunology Core Facility at Johns Hopkins Bloomberg School of Public Health for assistance in flow cytometry data acquisition and analysis, and they also thank Hoku West-Foyle from the Microscope Facility of Johns Hopkins University School of Medicine for assistance in wholemount pancreas data acquisition and analysis. Funding. This study was supported by the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases grants R56 DK123435 and R01DK125746 (D.F.), P30DK116073 (L.Y.), R01DK110183 (M.L.G.), and RO1DK084171 (G.W.W.) and the National Institute of General Medical Sciences grant R01 NS127292 (Hui. Li). The Zeiss confocal microscope was funded through NIH shared instrumentation grant S10OD016374. The MoFlo XDP cell sorter was funded through NIH grants S10OD016315 and S10RR13777001. This manuscript used data and tissue acquired from the Human Pancreas Analysis Program (HPAP-RRID:SCR_016202) Database (https://hpap.pmacs.upenn.edu), a Human Islet Research Network (RRID:SCR_014393) Consortium (UC4-DK-112217, U01-DK-123594, UC4-DK-112232, and U01-DK-123716). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. Z.G., D.K., C.X., G.W.W., and D.F. were responsible for antibody biodistribution. Z.G., D.K., M.L.G., and D.F. performed mouse pancreas immunohistology and flow cytometry as well as mouse islet and wholemount pancreas imaging. Z.G., C.M., M.N., L.Y., and D.F. were responsible for antigen preparation and mouse immunization. Z.G., C.M., and D.F. performed hybridoma screening. Z.G. and D.F. were responsible for mAb43 cloning and epitope mapping as well as recombinant antibody production. Hua Li and Hui. Li performed EM single-particle analysis. L.Y. and D.F. conceptualized the study. M.L.G. and D.F. wrote the manuscript. All authors read and edited the manuscript. D.F. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Publisher Copyright: {\textcopyright} 2023 by the American Diabetes Association.",
year = "2023",
month = feb,
doi = "10.2337/db22-0477",
language = "English (US)",
volume = "72",
pages = "184--195",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "2",
}