First-in-human study of high-dose gp96 in ALS: Safety and preliminary immunological effects

Xin Li; Fang Cheng; Zihao Wang; Rui Li; Chan Xing; Baifeng Wang; Shuman Xie; Ying Ju; Yuxiu Xu; Zhuojun Yin; Yan Mei; Shuang Yi; Dongqiang Ma; Xiaoran Li; Ying Luo; Buqing Ma; Hao Zhang; Changmei Liu; Xuyu Zhou; Dongsheng Fan; Yaqiang Jia; Zhenghui Hu; Zhonghua Zhou; Songdong Meng

doi:10.59717/j.xinn-med.2025.100157

The Innovation Medicine > 2025 Vol. 3 > No. 4 > 100157

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First-in-human study of high-dose gp96 in ALS: Safety and preliminary immunological effects

1.
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China
2.
University of Chinese Academy of Sciences, Beijing 101408, China
3.
Shenzhen HeatShock Biotech Co., Ltd, Shenzhen 518107, China
4.
AceMapAI Biotechnology, Suzhou 215000, China
5.
Department of Pharmacy, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China
6.
Department of Intensive Care Medicine, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China
7.
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology Chinese Academy of Sciences, Beijing 100101, China
8.
Department of Neurology, Peking University Third Hospital, Beijing 100191, China
9.
Tianjin Lhospital Medical Research Co., Ltd., Tianjin 300060, China
10.
Boao Evergrande International Hospital, Hainan 571400, China
11.
These authors contributed equally

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Corresponding author: mengsd@im.ac.cn
Received Date: April 01, 2025

Accepted Date: September 10, 2025

Published Online: September 11, 2025

The Innovation Medicine 3(4), https://doi.org/10.59717/j.xinn-med.2025.100157 | Cite this article

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PUBLIC SUMMARY
1. High-dose gp96 suppresses inflammatory CD14 monocytes, natural killer (NK) cells, and T cells in ALS patients.
  
  gp96 boosts regulatory T cells (Treg) and activated Treg (aTreg), enhancing their suppressive function.
  
  40% (4/10) of patients showed slower ALS Functional Rating Scale-Revised (ALSFRS-R) decline with gp96 therapy.
  
  gp96 efficacy links to Treg activation and reduced innate and effector T cell activity.

ABSTRACT

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with immune dysregulation. Based on the robust therapeutic effect and immunoregulatory capability of gp96 administration in the SOD1G93A mouse model, we conducted a prospective one-arm, open-label, proof-of-concept clinical trial in Hainan, China. High-dose gp96 was well tolerated in all 10 enrolled patients with ALS, and pronouncedly reduced the levels of inflammatory immune cells—CD14⁺ monocytes, NK cells, and CD4⁺ and CD8⁺ effector T cells—to levels comparable to those seen in healthy individuals. Treatment with gp96 also enhanced the suppressive function of Tregs and promoted the expansion of both activated Tregs and the CD38⁺LAG3⁺CXCR3^hiCD27^hi Treg subset. All participants experienced a slower decline in ALSFRS-R scores during the first 16 weeks post-treatment, and this slower decline was sustained in 40% (4/10) of patients at the end of follow-up in week 72. Treatment duration and Treg activation were positively correlated with the efficacy of gp96 treatment in alleviating the disease progression rate. These preliminary results emphasize the importance of the early identification of fast-progressing ALS patients and the need for long-term treatment. Our findings support further evaluation of gp96 as an immunomodulatory agent against ALS in randomized controlled trials with standardized outcome measures.

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Li X., Cheng F., Wang Z., et al. (2025). First-in-human study of high-dose gp96 in ALS: Safety and preliminary immunological effects. The Innovation Medicine 3:100157. https://doi.org/10.59717/j.xinn-med.2025.100157

Li X., Cheng F., Wang Z., et al. (2025). First-in-human study of high-dose gp96 in ALS: Safety and preliminary immunological effects. The Innovation Medicine 3:100157. https://doi.org/10.59717/j.xinn-med.2025.100157

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First-in-human study of high-dose gp96 in ALS: Safety and preliminary immunological effects

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