Directed Evolution of Genetically Encoded LYTACs for Cell-Mediated Delivery

Area of Science:

• Biotechnology
• Molecular Biology
• Therapeutic Development

Background:

• Lysosome-targeting chimeras (LYTACs) offer a method for extracellular protein degradation.
• Current LYTACs utilize synthetic glycopeptides, limiting their therapeutic integration and genetic encoding.
• A need exists for genetically encodable LYTACs for cellular applications and targeted delivery.

Approach:

• Designed a fully genetically encodable LYTAC (GELYTAC) by substituting the glycopeptide with insulin-like growth factor 2 (IGF2).
• Employed directed evolution to enhance GELYTAC potency and efficacy.
• Validated GELYTAC secretion from HEK293T cells and primary human T-cells.

Key Points:

• GELYTAC enables targeted protein degradation through a genetically encoded system.
• Engineered GELYTAC demonstrates enhanced potency via directed evolution.
• GELYTAC is secreted from therapeutic cells, facilitating targeted delivery and uptake.

Conclusions:

• GELYTAC represents a novel, genetically encodable tool for targeted protein degradation.
• Secretion of GELYTAC from engineered immune cells allows for spatially-selective therapeutic applications.
• This technology holds promise for advancing targeted protein degradation therapies.