The invention involves engineering a modified human cystathionine-γ-lyase enzyme to degrade methionine, an amino acid essential for cancer cell growth. This modified enzyme, with specific amino acid substitutions, offers enhanced catalytic activity, stability, and reduced immunogenicity, making it suitable for cancer treatment by depleting methionine in the body.
Background
Cancer cells have a heightened demand for the amino acid L-methionine, which is essential for their growth and survival. This dependency creates a therapeutic opportunity to target cancer cells by depleting methionine.
Traditional approaches have utilized bacterial methionine-γ-lyase enzymes to degrade methionine, but these enzymes pose significant challenges. They are highly immunogenic, leading to adverse immune responses, and have a short half-life, necessitating frequent and high dosing. These limitations hinder their clinical application and efficacy. There is a need for a more stable, less immunogenic enzyme that can effectively deplete methionine in cancer cells, thereby reducing tumor growth while minimizing side effects.
Technology description
The technology involves a modified protein with methionine-γ-lyase enzyme activity, specifically engineered from the human enzyme cystathionine-γ-lyase (CGL). This modified enzyme includes amino acid substitutions such as E59N, R119L, and E339V, enhancing its ability to degrade methionine, an amino acid crucial for cancer cell proliferation. The engineered proteins or their nucleic acids are intended for cancer treatment by depleting methionine. These proteins exhibit higher catalytic activity, improved serum stability, and reduced immunogenicity compared to bacterial methionine-γ-lyase, making them more suitable for therapeutic use. The technology also explores various formulations and delivery methods, including PEGylation, to extend the enzyme's half-life in the bloodstream.
This technology is differentiated by its focus on human-derived enzymes, which are less likely to provoke immune responses compared to bacterial counterparts. The engineered human methionine-γ-lyase (hMGL) variants exhibit significantly higher catalytic activity, allowing for lower therapeutic doses and potentially fewer side effects. By targeting a metabolic vulnerability specific to cancer cells, this approach offers a more selective treatment option, reducing side effects. The use of human enzymes also addresses the rapid deactivation and immunogenicity issues associated with bacterial enzymes, providing a more stable and effective cancer therapy.
Benefits
- Potential therapeutic application in cancer treatment by depleting methionine
- Enhanced catalytic activity for methionine degradation
- Improved serum stability and reduced immunogenicity
- Use of human enzyme variants to minimize immune response
- PEGylation to increase enzyme half-life in the bloodstream
- Versatile delivery methods and formulations for therapeutic use
- Potential to target a wide range of cancer types
- Engineered for higher therapeutic potency, requiring lower doses
- Reduced adverse reactions compared to bacterial enzymes
- Possibility of repeated dosing due to lower immunogenicity
Commercial applications
- Cancer treatment
- Pharmaceutical formulations
- Gene therapy vectors
- Protein engineering
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