Glycomimetic Siglec-7 Antagonists: A Sweet Approach to Cancer Immunotherapy

• Applicant: Professor Dr. Jonathan Cramer
• Subject Area: Pharmacy
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 572739635

Tumor cells have evolved the ability to evade immune surveillance by overexpressing ligands for immune checkpoint receptors. A blockade of these interactions has the potential to reactivate the dormant host immune system and eradicate the tumor. The successful implementation of cancer immunotherapy has marked a major breakthrough in the treatment of malignancies. However, a significant proportion of tumors are unresponsive to available immunotherapy approaches, highlighting the urgent demand for novel therapeutic strategies targeting alternative immune checkpoints and diversifying the range of targetable immune cells. Aberrant glycosylation is a widely conserved hallmark of cancer. By increasing the concentration of sialic acid-containing glycans in their glycocalyx (hypersialylation), tumor cells can exploit inhibitory sialic acid-binding immunoglobulin-like lectin receptors (Siglecs) to evade immune responses. Siglec-7 is the main sialic acid sensor on natural killer (NK) cells and, thus, represents a major glyco-immune checkpoint regulating NK cell activity. The expression of Siglec-7 ligands has been described for many cancer types, indicating a strong contribution of Siglec-7-signalling to tumor survival. This research project is aimed at the discovery of antagonists of the immune checkpoint Siglec-7, paving the way towards a new mode/mechanism of action for cancer immunotherapy. Employing the minimal Siglec-7 ligand N-acetyl neuraminic acid (Neu5Ac) as a template, structure–activity relationships in a cryptic hydrophobic pocket formed by the flexible CC′-loop will be explored. Furthermore, variations in the Neu5Ac glycerol side chain aimed at enhancing affinity while simultaneously improving physicochemical properties will be investigated. Siglec-7 antagonists will be evaluated by employing an extensive pipeline of biophysical assays to extract robust affinity estimates and elucidate ligand binding modes. Cellular assays will then provide quantitative information about the potential of these compounds to induce cytotoxic NK cell responses upon contact with Siglec-7 ligand-expressing tumor cells. Finally, an assessment of in vitro pharmacokinetic data will provide crucial information about physicochemical ligand properties, as well as metabolic stability, and pave the way towards further pre-clinical development.

• DFG Programme: Research Grants
• Major Instrumentation: HPLC-MS System
• Instrumentation Group: 1700 Massenspektrometer