Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?

Abstract

The disaccharide lactose is an excipient commonly used in pharmaceutical products. The two anomers, α- and β-lactose (α-L/β-L), differ by the orientation of the C-1 hydroxyl group on the glucose unit. In aqueous solution, a mutarotation process leads to an equilibrium of about 40% α-L and 60% β-L at room temperature. Beyond a pharmaceutical excipient in solid products, α-L has immuno-modulatory effects and functions as a major regulator of TIM-3/Gal-9 immune checkpoint, through direct binding to the β-galactoside-binding lectin galectin-9. The blockade of the co-inhibitory checkpoint TIM-3 expressed on T cells with anti-TIM-3 antibodies represents a promising approach to combat different onco-hematological diseases, in particular myelodysplastic syndromes and acute myeloid leukemia. In parallel, the discovery and development of anti-TIM-3 small molecule ligands is emerging, including peptides, RNA aptamers and a few specifically designed heterocyclic molecules. An alternative option consists of targeting the different ligands of TIM-3, notably Gal-9 recognized by α-lactose. Modulation of the TIM-3/Gal-9 checkpoint can be achieved with both α- and β-lactose. Moreover, lactose is a quasi-pan-galectin ligand, capable of modulating the functions of most of the 16 galectin molecules. The present review provides a complete analysis of the pharmaceutical and galectin-related biological functions of (α/β)-lactose. A focus is made on the capacity of lactose and Gal-9 to modulate both the TIM-3/Gal-9 and PD-1/PD-L1 immune checkpoints in oncology. Modulation of the TIM-3/Gal-9 checkpoint is a promising approach for the treatment of cancers and the role of lactose in this context is discussed. The review highlights the immuno-regulatory functions of lactose, and the benefit of the molecule well beyond its use as a pharmaceutical excipient.

Glycomimetics for the inhibition and modulation of lectins

“…314 The activity of the TIM-3/Gal-9 checkpoint can be modulated in two ways: (i) blockage of TIM-3 with monoclonal antibodies or small molecules and (ii) blockage of Gal-9. 315 Three monoclonal antibodies to TIM-3 are already in clinical trials for the treatment of solid tumours. Each of the programmes is evaluating the safety and efficacy either as monotherapy or in combination with anti-PD-1 antibodies in patients with advanced solid tumours or hematologic malignancies.…”

Cancer‐derived non‐coding RNAs endow tumor microenvironment with immunosuppressive properties

“…T cell immunoglobulin and mucin domain 3 (TIM‐3), as a promising immune checkpoint, interacts with its ligand galectin 9 (Gal‐9) to negatively regulate the antitumor immunity (Bailly et al, 2021). Therefore, cancer cells overexpress Gal‐9 on their surfaces through ncRNA mechanisms, enabling TME to acquire immunosuppressive properties (L. Zhao, Cheng, et al, 2021).…”

Inhibition of galectins in cancer: Biological challenges for their clinical application

“…In this sense, we have some clues for certain galectins. For instance, galectin-1 downregulation in transformed ( 17 , 123 , 131 – 135 ) and tumor-associated stroma cells ( 46 , 47 , 125 , 126 , 136 ) have demonstrated beneficial effects in pre-clinical studies. Therefore, these reports clarify the cellular targets where galectin-1 should be inhibited to obtain beneficial anti-tumor effects.…”