Targeted degradation of glycoimmune checkpoints Siglec-7 and -9 for cancer immunotherapy

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT Targeted degradation of extracellular proteins is a new direction in drug discovery. In this approach, a heterobifunctional molecule is used to recruit a target protein of interest to the proteosome or lysosome for degradation. Typically, only one membrane protein can be targeted for degradation at a time. Using SuFEx click chemistry, we have discovered a ligand that binds with exclusive specificity to the newly discovered glycoimmune checkpoints Siglec-7 and -9. In this project, we will test the hypothesis that a heterobifunctional degrader constructed with such ligands can simultaneously target both Siglecs to the lysosome for degradation. In the tumor microenvironment, Siglec-7 and Siglec-9 are predominantly expressed by myeloid cells, the most abundant immune cells infiltrating solid tumors, including melanoma and pancreatic cancer. These Siglecs are not only involved in suppressing macrophage-mediated phagocytosis of tumor cells, but also in inhibiting T cell activity, operating in a way which is orthogonally to CTLA-4 and PD-1. When T cells interact with neighboring myeloid cells, such as dendritic cells and macrophages, they acquire Siglec-7 and -9 through a process called trogocytosis, resulting in impaired T cell activation and effector function. Therefore, we hypothesize that degradation of Siglec-7 and -9 could be used alone or in combination with FDA-approved immune checkpoint blockade to treat anti-PD-1 or anti-CTLA-4 refractory tumors In Aim 1 of this project, we will construct an unnatural sialic acid derivative library and use a cell-based assay to identify improved ligands with high affinity and exclusive specificity for Siglec-7 and Siglec-9. These optimized ligands will be used to construct degraders that specifically target and degrade both Siglecs. The degradation efficacy, pharmacokinetics and toxicity of these degraders will be determined. Subsequently, the therapeutic potential and mechanism of action of the degraders will be evaluated both in vitro and in humanized mouse tumor models with a focus on melanoma and pancreatic cancer (Aim 2). The degraders will be tested alone or in combination with other immunomodulatory agents, such as anti-PD-1 or anti-CTLA-4. Finally, in Aim 3, the ability of these degraders to induce Siglec-7 and -9 degradation will be further investigated using cultured pancreatic cancer patient tumor slices. The resulting effects on macrophage- and T- cell-mediated tumor control will be examined.

Public health relevance public domain (NIH RePORTER)

RELEVANCE / PROJECT NARRATIVE If successful, this project will offer highly innovative and translatable agents and tools for treating solid tumors such as melanoma and pancreatic cancer. These agents may also be used in combination with FDA- approved immunotherapies, such as immune checkpoint blockade, to achieve a better patient response rate.