First-in-human clinical trial of the NKT cell-stimulatory glycolipid OCH in multiple sclerosis

Wakiro Sato; Daisuke Noto; Manabu Araki; Tomoko Okamoto; Youwei Lin; Hiromi Yamaguchi; Ryoko Kadowaki-Saga; Atsuko Kimura; Yukio Kimura; Noriko Sato; Takami Ishizuka; Harumasa Nakamura; Sachiko Miyake; Takashi Yamamura

doi:10.1177/17562864231162153

First-in-human clinical trial of the NKT cell-stimulatory glycolipid OCH in multiple sclerosis

Ther Adv Neurol Disord. 2023 Mar 23:16:17562864231162153. doi: 10.1177/17562864231162153. eCollection 2023.

Authors

Wakiro Sato¹, Daisuke Noto^{1

2}, Manabu Araki³, Tomoko Okamoto⁴, Youwei Lin⁴, Hiromi Yamaguchi¹, Ryoko Kadowaki-Saga¹, Atsuko Kimura¹, Yukio Kimura⁵, Noriko Sato⁵, Takami Ishizuka⁶, Harumasa Nakamura⁶, Sachiko Miyake², Takashi Yamamura^{7

3}

Affiliations

¹ Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.
² Department of Immunology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Japan.
³ Multiple Sclerosis Center, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.
⁴ Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.
⁵ Department of Radiology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.
⁶ Translational Medical Center, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.
⁷ Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.

Abstract

Background: Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that causes the damage to the myelin sheath as well as axonal degeneration. Individuals with MS appear to have changes in the numbers and functions of T-cell subsets, leading to an immunological imbalance accompanied by enhanced autoreactivity. In previous preclinical studies, (2 S,3 S,4R)-1-O-(α-D-Galactopyranosyl)-N-tetracosanoyl-2-amino-1,3,4-nonanetriol (OCH), a synthetic analog of α-galactosylceramide stimulatory for invariant NKT (iNKT) cells, has shown therapeutic or disease-preventive immunoregulatory effects in autoimmune disease models such as experimental autoimmune encephalomyelitis (EAE).

Objectives: This study is the first-in-human study of oral OCH to evaluate the pharmacokinetics and to examine the effects on immune cells as well as related gene expression profiles.

Methods: Fifteen healthy volunteers and 13 MS patients who met the study criteria were enrolled. They were divided into five cohorts and received oral administration of various doses of granulated powder of OCH (0.3-30 mg), once per week for 4 or 13 weeks. Plasma OCH concentrations were measured by high-performance liquid chromatography. Frequencies of lymphocyte subsets in peripheral blood were evaluated by flow cytometry, and microarray analysis was performed to determine OCH-induced changes in gene expression.

Results: Oral OCH was well tolerated, and its bioavailability was found to be sufficient. Six hours after a single dose of OCH, increased frequencies of Foxp3⁺ regulatory T-cells were observed in some cohorts of healthy subjects and MS patients. Furthermore, gene expression analysis demonstrated an upregulation of several immunoregulatory genes and downregulation of pro-inflammatory genes following OCH administration.

Conclusion: This study has demonstrated immunomodulatory effects of the iNKT cell-stimulatory drug OCH in human. Safety profiles together with the presumed anti-inflammatory effects of oral OCH encouraged us to conduct a phase II trial.

Keywords: OCH; Treg cells; clinical trial; iNKT cells; multiple sclerosis.