Chemical glycobiology tool development: Proximity-based modalities

Stanford University, Stanford CA

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY This is a renewal application of R01GM058867 which has supported our foundational efforts in chemical glycobiology tool development since 1999. Our current goal is to leverage glycochemistry and glycobiology in the development of proximity-based technologies for use in basic research and drug development. Molecules designed to induce neo-interactions among biomolecules are now well- established research tools and emerging clinical candidates. This paradigm is embodied by proteolysis-targeting chimeras (PROTAC), bifunctional molecules that form ternary complexes with target proteins and E3 ligase enzymes, leading to their degradation by the proteasome. Targeted protein degradation mediated by PROTACs is a powerful platform technology for basic research and for drug development. But this approach is limited to intracellular proteins; extracellular proteins that are secreted or plasma membrane-associated are mostly inaccessible to PROTAC-mediated degradation. In the previous granting period, we leveraged glycan- binding lysosomal trafficking receptors in a new modality for targeted degradation of extracellular proteins called lysosome-targeting chimeras (LYTACs). These comprised a target binder (e.g., antibody or nanobody) linked to a glycan-based ligand that engages either the ubiquitously expressed cation-independent mannose-6-phosphate receptor (M6PR) or the liver- specific asialoglycoprotein receptor (ASGPR). We developed LYTACs for both soluble and membrane-associated proteins of therapeutic relevance, and we used the LYTAC platform as a research tool alongside CRISPR screens to define cellular determinants of lysosomal trafficking and protein degradation. In the next funding period, we will build upon this work with three specific Aims. In Aim 1, we will develop tumor-immune cell targeted chimeras (TICTACs) as a new modality for cancer immune therapy. These molecules are intended to deplete immune checkpoint receptors from tumor-associated macrophages via internalization without affecting peripheral macrophages, thereby mitigating autoimmune toxicities. In Aim 2, we will develop LYTAC-antibody-drug conjugates (LYTAC-ADCs) that incorporate lysosomal trafficking receptor ligands into the ADC structure. The LYTAC component will drive internalization, thereby expanding the ADC target space to include cancer antigens that are inherently poor internalizers. Finally, in Aim 3 we will develop trogocytosis-targeting chimeras (TrogoTACs) as a new proximity-based modality for targeted protein transfer from one cell type to another.