The invention involves engineering a modified enzyme, cystathionine-gamma-lyase, to degrade L-cyst(e)ine, targeting cancer cells reliant on this amino acid. The enzyme exhibits improved stability and reduced immunogenicity, making it suitable for therapeutic applications in cancer treatment.
Cancer cells often exhibit altered metabolic requirements compared to normal cells, relying heavily on specific amino acids for growth and survival. L-cysteine and its oxidized form, L-cystine, are crucial for various cellular functions, including protein synthesis and maintaining redox balance through glutathione production. Certain cancers, such as prostate and small cell lung carcinomas, have been shown to depend on extracellular cysteine/cystine, partly due to the overexpression of the xCT cystine/glutamate antiporter. This dependency suggests a potential therapeutic target, as depriving cancer cells of cysteine/cystine could inhibit their growth.
Current strategies, like using small molecule inhibitors to block cystine uptake, have shown promise but are limited by the ability of tumor cells to acquire cysteine through alternative pathways, such as direct uptake from the microenvironment. Moreover, no existing therapies utilize enzymes to irreversibly degrade cysteine/cystine in a manner suitable for human application, highlighting the need for novel approaches that can effectively and selectively target this metabolic vulnerability in cancer cells.
The technology involves engineering a protein with L-cyst(e)ine degrading enzyme activity, specifically a modified cystathionine-γ-lyase. This enzyme is enhanced through amino acid substitutions to improve its ability to degrade L-cyst(e)ine, a critical amino acid for certain cancer cells. The modified enzyme exhibits improved enzymatic properties, reduced immunogenicity, and increased serum stability, making it suitable for therapeutic applications.
The technology also includes compositions and methods for treating cancer by depleting L-cyst(e)ine, thereby targeting tumors that rely on this amino acid for growth. The engineered enzymes can be formulated with pharmaceutical carriers and linked to molecules like polyethylene glycol (PEG) to enhance stability and efficacy in medical treatments. Additionally, nucleic acids encoding these enzymes, vectors for expression, and host cells for production are part of the technology.
This technology is differentiated by its focus on engineering a human or primate enzyme, minimizing the risk of immune responses that can occur with non-human proteins. By modifying cystathionine-γ-lyase, a naturally occurring human enzyme, the technology leverages a familiar biological scaffold to create a therapeutic agent with high specificity and activity for L-cyst(e)ine degradation. This approach allows for repeated dosing and increased therapeutic efficacy in cancer treatment.
The ability to deplete both L-cystine and L-cysteine systemically offers a comprehensive strategy to deprive tumors of essential nutrients, potentially overcoming limitations of existing therapies that target only one form of the amino acid. The use of PEGylation further enhances the enzyme's stability and circulatory persistence, making it a robust candidate for clinical applications.