An Oral PROTAC Targeting HPK1 Degradation Potentiates Anti-Solid Tumor Immunity

Yuejun Yao; Mingfei Wu; Yanfang Wang; Ziyan Liao; Yinxian Yang; Yun Liu; Jiaqi Shi; Wei Wu; Xinwei Wei; Jianchang Xu; Yugang Guo; Xiaowu Dong; Jinxin Che; Jinqiang Wang; Zhen Gu

doi:10.1002/adma.202411454

An Oral PROTAC Targeting HPK1 Degradation Potentiates Anti-Solid Tumor Immunity

Adv Mater. 2024 Nov 20:e2411454. doi: 10.1002/adma.202411454. Online ahead of print.

Authors

Yuejun Yao^{1

2

3}, Mingfei Wu^{1

4}, Yanfang Wang^{1

2

3}, Ziyan Liao^{1

2

3}, Yinxian Yang^{1

2

3}, Yun Liu^{1

2

3}, Jiaqi Shi^{1

2

3}, Wei Wu⁵, Xinwei Wei^{1

2

3}, Jianchang Xu^{1

2

3}, Yugang Guo^{1

6}, Xiaowu Dong^{1

4

7}, Jinxin Che^{1

4}, Jinqiang Wang^{1

2

3

7}, Zhen Gu^{1

2

3

8

9

10

11}

Affiliations

¹ National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
² Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
³ Jinhua Institute of Zhejiang University, Jinhua, 321299, China.
⁴ Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
⁵ Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
⁶ Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
⁷ Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009, China.
⁸ Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou, 310000, China.
⁹ MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China.
¹⁰ Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
¹¹ Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou 310029, China, Liangzhu Laboratory, Hangzhou, 311121, China.

PMID: 39568237
DOI: 10.1002/adma.202411454

Abstract

Hematopoietic progenitor pinase1 (HPK1) knockout has been identified as an efficient route to enhance anti-tumor immune response. Here, this work develops an oral proteolysis targeting chimera (PROTAC) targeting HPK1 to efficiently and selectively degrade HPK1 to augment immunotherapeutic outcomes. In a postoperative tumor model of human cervical cancer in NSG mice, the orally-administrated PROTAC can reach tumors, down-regulate HPK1 levels in locally-administrated CAR-T cells, and promote their efficiency in inhibiting solid tumor recurrence, achieving 50% partial response (PR) and 50% complete response (CR). In addition, oral administration of PROTAC can amplify the suppression capability of the anti-PD-L1 antibody on the growth of CT26 solid tumors in BALB/c mice by promoting the infiltration of CD45-positive immune cells from 0.7% to 1.5% and CD3-positive T cells from 0.2% to 0.5% within the tumors.

Keywords: HPK1 PROTAC; drug delivery; immunotherapy; oral administration; solid tumor.

Abstract

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