Project Background
A biopharmaceutical startup aimed to target the EGFR in KRAS-mutant cancer models. While intracellular inhibitors face resistance, the client sought a LYTAC strategy to degrade the extracellular and membrane-bound EGFR. The primary challenge was the design of a stable bifunctional molecule that could simultaneously bind the EGFR extracellular domain and the Cation-Independent Mannose-6-Phosphate Receptor (CI-M6PR) without triggering premature systemic clearance or off-target glycan interactions.
Our Support
We designed a customized LYTAC platform utilizing a high-affinity EGFR antibody as the "warhead" and a chemically synthesized M6P-based glycan cluster as the lysosome-targeting ligand. Our team optimized the conjugation chemistry using site-specific GlycoConnect™-like technology to ensure a precise ligand-antibody ratio (LAR). We evaluated multiple linker lengths and PEG-based compositions to balance hydrophilicity and binding kinetics. Through live-cell imaging and lysosomal colocalization assays, we confirmed that the lead LYTAC candidate efficiently shuttled EGFR into the lysosomal compartment. The final molecules achieved over 85% degradation of total EGFR in A431 cell lines at nanomolar concentrations, successfully bypassing the limitations of traditional tyrosine kinase inhibitors.
Client Testimonial
The technical depth provided by the BOC Sciences team in glycan synthesis and site-specific conjugation was instrumental. Their LYTAC development platform allowed us to transition from a theoretical target to a validated lead candidate with clear lysosomal degradation evidence in an exceptionally short timeframe.
Project Background
An innovative R&D group focused on neuro-oncology required a degradation solution for a specific "undruggable" cell surface glycoprotein associated with tumor immune evasion. The target lacked deep hydrophobic pockets for small-molecule binding, making PROTACs unfeasible. The client needed a LYTAC approach but faced difficulties in selecting an appropriate lysosome-shuttling receptor that is highly expressed in the target tissue to ensure selective protein internalisation and degradation.
Our Support
To address this, we first conducted a receptor expression profiling to identify the Asialoglycoprotein Receptor (ASGPR) as the optimal shuttling vehicle for this liver-adjacent tumor model. We then developed a Tri-GalNAc-based LYTAC system. Our researchers synthesized a series of GalNAc clusters with varying branching architectures to maximize binding avidity to ASGPR. By screening different conjugation sites on the target-binding peptide, we preserved the binding affinity of the warhead while enhancing the complex's internalisation rate. Quantitative proteomics (TMT-labeling MS) was employed to verify the proteome-wide selectivity of the degradation. We delivered five optimized LYTAC candidates that demonstrated potent target depletion and significant inhibition of downstream signaling pathways in primary cell cultures.
Client Testimonial
BOC Sciences' expertise in ASGPR-mediated delivery and complex glycan chemistry provided the breakthrough we needed. Their systematic optimization of the Tri-GalNAc structure and rigorous mass spectrometry validation gave us full confidence in the selectivity and efficacy of our new degradation pipeline.
Addresses Extracellular and Membrane Protein Targets
