Design, Synthesis, and Biological Evaluation of Small, High-Affinity Siglec‑7 Ligands: Toward Novel Inhibitors of Cancer Immune Evasion

Natural
killer cells are able to directly lyse tumor cells, thereby
participating in the immune surveillance against cancer. Unfortunately,
many cancer cells use immune evasion strategies to avoid their eradication
by the immune system. A prominent escape strategy of malignant cells
is to camouflage themselves with Siglec-7 ligands, thereby recruiting
the inhibitory receptor Siglec-7 expressed on the NK cell surface
which subsequently inhibits NK-cell-mediated lysis. Here we describe
the synthesis and evaluation of the first, high-affinity low molecular
weight Siglec-7 ligands to interfere with cancer cell immune evasion.
The compounds are Sialic acid derivatives and bind with low micromolar Kd values to Siglec-7. They display up to a 5000-fold
enhanced affinity over the unmodified sialic acid scaffold αMe
Neu5Ac, the smallest known natural Siglec-7 ligand. Our results provide
a novel immuno-oncology strategy employing natural immunity in the
fight against cancers, in particular blocking Siglec-7 with low molecular
weight compounds.