Bifunctional molecules for lysosomal targeting and related compositions and methods
Inventors
Bertozzi, Carolyn R. • Banik, Steven • Pedram, Kayvon • Ahn, Green
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Assignees
Leland Stanford Junior University
MemberStanford UniversityStanford UniversityTodd Coleman is an associate professor of bioengineering at Stanford University. His research combines applied probability, physiology, and bioelectronics to develop methods and devices for monitoring and modulating nervous-system and other physiological activity, including brain and visceral-organ signals.
Todd Coleman is an associate professor of bioengineering at Stanford University. His research combines applied probability, physiology, and bioelectronics to develop methods and devices for monitoring and modulating nervous-system and other physiological activity, including brain and visceral-organ signals.
Publication Number
US-12753239-B2
Publication Date
2026-10-06
Expiration Date
Abstract
Provided are bifunctional molecules that include a first moiety that specifically binds a cell surface molecule or extracellular molecule, and a second moiety that specifically binds a lysosomal targeting molecule. The bifunctional molecules find use, e.g., for targeted degradation of cell surface and extracellular molecules (e.g., proteins) via the endosomal/lysosomal pathway. Also provided are compositions and kits that include the bifunctional molecules, as well as methods of using the bifunctional molecules. Methods of making bifunctional molecules are also provided.
Core Innovation
The invention provides a bifunctional molecule comprising a first moiety that comprises a protein specifically binding a cell surface molecule or extracellular molecule, and a second moiety comprising a polymer scaffold displaying one or more ligands specifically binding an asialoglycoprotein receptor (ASGPR). The ligands are selected from N-acetylgalactosamines (GalNAc), galactose, and glucose, and a linker conjugates the first and second moieties. The disclosed embodiments shuttle bound targets into hepatocyte lysosomes for degradation.
The disclosure describes polymer-mediated cellular uptake, antibody conjugation, and ASGPR-mediated internalization and lysosomal trafficking of protein conjugates in HepG2 and Huh7 cells. It reports target-protein reduction involving EGFR, CD71, and PD-L1, including cetuximab-GalNAc-mediated EGFR degradation and trastuzumab-GalNAc-mediated HER2 reduction. The background section is not included in the partial content, so the problem being solved is not explicitly described in the patent.
Claims Coverage
The provided relevant claims identify one independent claim directed to a bifunctional molecule comprising three inventive features.
Protein that specifically binds a cell surface or extracellular molecule
The first moiety comprises a protein that specifically binds a cell surface molecule or an extracellular molecule.
Polymer scaffold displaying ASGPR-binding ligands
The second moiety comprises a polymer scaffold displaying one or more ligands that specifically bind an asialoglycoprotein receptor (ASGPR), wherein the ligands are selected from N-acetylgalactosamines (GalNAc), galactose, and glucose.
Linker conjugation of the moieties
A linker conjugates the first moiety and the second moiety.
The independent claim covers all elements of the claim as a target-binding protein moiety and an ASGPR-ligand-displaying polymer scaffold conjugated via a linker.
Stated Advantages
The description reports increased cargo uptake with GalNAc-containing conjugates.
The description reports EGFR degradation in HEP3B and HepG2 cells and states that GalNAc conjugates outperform M6PR-ligand conjugates in HEP3B cells.
Documented Applications
The document identifies therapeutic applications including liver cancer and fibrosis.
GalNAc-containing protein conjugates show uptake in hepatocyte-derived cells such as HepG2 and Huh7 cells, with ASGPR-mediated uptake and lysosomal trafficking demonstrated.
Target-protein reduction is documented for EGFR, CD71, and PD-L1, including EGFR reduction following cetuximab-GalNAc treatment in HEP3B cells and HER2 reduction following trastuzumab-GalNAc treatment.
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