Targeting the Untapped Extracellular Proteome:

The Next Wave of Protein Degradation

Interest in the field of protein degradation continues to grow, as classical approaches to developing small molecule and biologic therapeutics have proven to be ineffective at addressing certain disease-relevant targets. Protein degradation offers the potential to eliminate disease-causing proteins.

First-generation protein degradation development has focused on ligase-targeting bispecific molecules. However, extracellular and secreted proteins – which represent 40% of the human proteome – are not accessible with these approaches, which can only degrade intracellular proteins.

Our proprietary LYTAC—Lysosomal Targeting Chimera—platform enables targeted degradation of the untapped extracellular proteins. Our LYTAC platform is designed to enable the depletion of (versus the inhibition of) of many targets previously considered undruggable, and the development of novel therapeutics for currently underserved patient populations.

THE OVERVIEW

Our Approach: Leveraging
Lysosomal Degradation

Our aim is to inhibit the function of pathogenic proteins by degrading them to treat disease. The mannose-6-phosphate receptor (M6PR) is a cell-surface glycoprotein that acts as a lysosomal trafficking shuttle.

As shown in this graphic to the left, M6PR ligands bind M6PR and are internalized and shuttled through the endosome-lysosome pathway into the degradation compartments.

Central to our approach, we hijack this naturally occurring lysosomal trafficking shuttle process by linking an extracellular target binder to an M6PR ligand. The M6PR then drags the ligand with its linked extracellular target into lysosomes for degradation. The platform extends beyond M6PR, and we have established LYTACs with multiple receptor systems for both broad-based and tissue-specific targeting.

While the graphic to the left shows an antibody target binder, the original modality explored with this method, we have expanded target binders to include low molecular weight/small molecules and bispecific antibodies.

To date, we have generated hundreds of LYTACs across multiple modalities.

Applications

New opportunities to address currently undruggable targets

LYTACs can uniquely address extracellular targets that remain challenging for antibody and small molecule modalities.

soluble proteins
  • Pathogenic Proteins/Aggregates
  • Large complexes and possibly aggregated fibers
  • Pathogenic antibodies (without global immune
    suppression)
  • Neutralizing antibodies that render therapies
    less effective
membrane proteins
  • Targets with multiple functional partners or epitopes
  • Targets with unknown signaling partner(s)
  • Targets where it has been challenging to identify
    specific and functional binders
  • Receptors with constitutively active signaling

lytacs can expand epitope space by leveraging neutral (non-functional) antibody and sm binders

 

Advancing a Robust Discovery Pipeline

The accumulation of proteins and immune complexes leads to a slew of diseases – from autoimmune and inflammatory conditions to cancer to neurodegenerative diseases – and thus a broad array of potential applications for our extracellular protein degradation technology. To that end, we are advancing an undisclosed discovery pipeline of novel LYTAC degraders toward the clinic.

Some of the applications we will pursue on our own or in partnership include:

Scientific Publications

Lysosome-targeting chimeras for degradation of extracellular proteins

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LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation

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Read All News

Strategic Partners

Lilly Collaboration: Expanding the Potential Impact of the LYTAC Platform

In August 2021, we announced a multi-year research collaboration and licensing agreement with Eli Lilly and Company focused on the discovery, development and commercialization of novel targeted therapeutics using our LYTAC technology.

Under the terms of the agreement, Lycia and Lilly are utilizing Lycia’s LYTAC platform to discover and develop novel degraders for up to five targets that aim to address key unmet medical needs in Lilly’s therapeutic areas of focus, including immunology and pain. Lilly is solely responsible for preclinical and clinical development of candidates and receives an exclusive worldwide license to commercialize potential medicines resulting from the agreement.

Lycia received an upfront payment of $35 million. We are also eligible to receive over $1.6 billion in potential milestone payments based on the achievement of prespecified preclinical, development and commercial milestones, as well as tiered royalties from mid-single to low double-digits on sales resulting from the agreement.

Interested in partnering with us? Contact bd@lyciatx.com