Cell-type specific enzymatic degradation of pathological mucins

Targeted protein degradation is an emerging strategy for the elimination of classically undruggable proteins. Mucins are known to be involved in tumor-progressive pathways but are difficult to target using small molecules and antibodies. To overcome this issue, Nobel laureate Carolyn Bertozzi and her research team have engineered a cancer antigen-targeting mucin-specific protease (novel composition of matter) to degrade cell surface mucins on cancer cells and other cells in which aberrant mucin expression drives pathology. Fusion of the engineered mucinase variant to a cancer antigen-binding nanobody resulted in selective demucination of cancer cells,

Mucins have remained canonically undruggable. Therapeutic interventions face the challenge that mucin signaling occurs through the cooperative action of hundreds of arrayed epitopes and a unique, scaffolding secondary structure. There is no catalytic site to inhibit with a small molecule, nor is there a single binding site to block with an antibody. By bringing a protease directly to disease-driving mucins, we bypass these challenges via targeted protein degradation (TPD) of these unwanted molecules. This invention will further the development of biologics which degrade specific glycoforms of cell surface targets.

These enzyme conjugates can be a platform technology for a new class of cell type- and target-specific TPD therapeutics.

Stage of Development