A Granzyme B-Cleavable T Cell-Targeted Bispecific Cell Vesicle Connector for Reversing New-Onset Type 1 Diabetes

Yanfang Wang; Yanping Sun; Xiuwen Zhang; Shenqiang Wang; Xuehui Huang; Kairui Xu; Yun Liu; Yingqi Huang; Jianchang Xu; Xinwei Wei; Hao Cheng; Liqiang Pan; Jinqiang Wang; Zhen Gu

doi:10.1021/jacs.4c13644

A Granzyme B-Cleavable T Cell-Targeted Bispecific Cell Vesicle Connector for Reversing New-Onset Type 1 Diabetes

J Am Chem Soc. 2025 Jan 27. doi: 10.1021/jacs.4c13644. Online ahead of print.

Authors

Yanfang Wang¹, Yanping Sun¹, Xiuwen Zhang¹, Shenqiang Wang¹, Xuehui Huang^{1

2}, Kairui Xu¹, Yun Liu¹, Yingqi Huang¹, Jianchang Xu¹, Xinwei Wei^{1

2}, Hao Cheng³, Liqiang Pan¹, Jinqiang Wang^{1

2

4

5}, Zhen Gu^{1

2

4

6

7

8

9}

Affiliations

¹ State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
² Jinhua Institute of Zhejiang University, Jinhua 321299, China.
³ Department of Materials Science and Engineering, Drexel University, Philadelphia, Pennsylvania 19104, United States.
⁴ Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
⁵ Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
⁶ Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.
⁷ Liangzhu Laboratory, Hangzhou 311121, China.
⁸ Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou 310058, China.
⁹ MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China.

PMID: 39869523
DOI: 10.1021/jacs.4c13644

Abstract

Type 1 diabetes (T1D) is an autoimmune disorder in which pancreatic β-cells are destroyed by CD8⁺ T cells. Anti-CD3 antibody effectively treats early-stage T1D when β-cell autoantibodies are detected but before symptoms appear. However, it impairs the immune system temporarily, exposing individuals to infection. A therapeutic that can reverse new-onset T1D without harming the immune system remains urgently needed. Herein, we have constructed cellular vesicles presenting granzyme B-responsive fusion proteins (designated aCD8-GrzBcs-IL2) composed of a single-chain variable fragment of anti-CD8 antibodies and a mutein interleukin-2 (IL2). aCD8-GrzBcs-IL2 is designed to simultaneously inhibit CD8⁺ T cells and promote Treg cells, especially when CD8⁺ T cells are attacking β-cells. In vitro, these cellular vesicles can inhibit the cell-killing effect of CD8⁺ T cells and enhance the expansion of Treg cells. Notably, intravenous administration of aCD8-GrzBcs-IL2-expressed cellular vesicles reversed newly onset diabetes in 77.8% of nonobese diabetic (NOD) mice without reducing blood CD3⁺ T cells and CD8⁺ T cells, indicating a favorable safety profile.