Engineered SGPL1 enzymes for selective extracellular S1P depletion in cancer immunotherapy

Background

The sphingosine-1-phosphate (S1P) signaling axis plays a pivotal role in regulating immune cell trafficking, particularly in the context of cancer immunotherapy. S1P gradients between tumor-draining lymph nodes and the tumor micro­environ­ment govern lymphocyte migration, with elevated extracellular S1P concentrations leading to lymphocyte retention, immune suppression, and resistance to checkpoint blockade therapies. Restoring effective lymphocyte circulation and tumor infiltration requires new strategies capable of selectively depleting extracellular S1P while minimizing systemic toxicity.

Current pharmacological strategies, including sphingosine kinase (SPHK) inhibitors and anti-S1P monoclonal antibodies, face notable shortcomings. SPHK inhibitors often lack selectivity, exhibit poor solubility, and impact both intra- and extracellular S1P pools, raising toxicity concerns. Antibody-based approaches neutralize circulating S1P but suffer from rapid clearance and limited tumor penetration, ultimately failing to sustain deep extracellular S1P depletion. These limitations restrict the effectiveness of current approaches to enhance immune cell mobilization and improve cancer immunotherapy outcomes.

Technology overview

This technology features engineered sphingosine-1-phosphate lyase (SGPL1) enzymes designed to selectively degrade extracellular S1P for therapeutic immune modulation. Built on human or prokaryotic backbones, the enzymes incorporate targeted deletions of transmembrane domains, stabilizing point mutations, and optimized glycosylation sites to enhance solubility, manu­facturability, and circulatory half-life. The engineered proteins retain their specific lyase activity against S1P while minimizing effects on intracellular pools.

Administered systemically, the enzymes deplete extracellular S1P, promoting lymphocyte egress from tumor-draining lymph nodes and enhancing CD8+ T cell infiltration into tumors. Refinements in production balance yield, stability, and immunogenicity risks. Preclinical studies demonstrate robust reductions in serum and tissue S1P levels, accompanied by significant tumor growth suppression. The modular platform also offers potential for broader applications in enzyme replacement therapies and fibrotic disease treatment.

Benefits

• Selectively depletes extracellular S1P to enhance immune cell trafficking and tumor infiltration
• Avoids disruption of intracellular S1P, reducing systemic toxicity risks
• Improved circulatory half-life and manufacturability through glycosylation and stabilization strategies
• Superior depth of extracellular S1P depletion compared to small molecule inhibitors and antibodies
• Modular platform adaptable for enzyme replacement and fibrotic disease therapies

Commercial applications

• Cancer immunotherapy enhancement
• Combination therapies with immune checkpoint inhibitors
• Enzyme replacement for sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS)
• Fibrotic disease treatment targeting S1P signaling
• Immune cell trafficking modulation for solid tumors

Opportunity

• Overcomes key limitations of existing S1P-targeting therapies by providing deep, selective extracellular depletion
• Supports improved immunotherapeutic efficacy through enhanced lymphocyte mobilization
• Available for licensing to biopharma partners developing next-generation immunotherapies, enzyme therapeutics, and fibrosis treatments

Intellectual property

WO2025090890 – Compositions of engineered human and prokaryotic S1P lyase enzymes and methods for treating disease