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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.

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