This invention describes engineered kynureninase enzymes that degrade kynurenine, a metabolite linked to cancer progression. These enzymes, optimized for human therapy, can be modified with polyethylene glycol to enhance stability and circulation, offering potential in cancer treatment when combined with other therapies like immunotherapy.
Cancer cells often evade the immune system by exploiting the kynurenine pathway, which involves the metabolism of tryptophan into kynurenine by enzymes such as indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). This metabolic pathway leads to an accumulation of kynurenine, an immunosuppressive metabolite that can inhibit T cell proliferation and induce regulatory T cell differentiation, promoting tumor tolerance and immune escape.
Current therapeutic strategies targeting this pathway include small molecule inhibitors of IDO and TDO, which aim to reduce kynurenine levels and restore immune function. However, these inhibitors often face challenges such as off-target effects, limited efficacy due to the presence of multiple enzyme isoforms, and the potential for paradoxical upregulation of IDO expression. These limitations highlight the need for more effective approaches to deplete kynurenine and enhance anti-tumor immunity.
The technology utilizes proteins with kynureninase activity to degrade kynurenine, a metabolite involved in cancer progression. These proteins can be modified to enhance their activity and are used therapeutically to reduce kynurenine levels during cancer treatment. The technology includes the development of both bacterial and mammalian engineered kynureninase enzymes optimized for human therapy, which can be linked to polyethylene glycol (PEG) for increased stability and circulation time in the body, enhancing therapeutic efficacy and minimizing immunogenicity. These enzymes can be used alongside other cancer therapies, such as immunotherapy, to improve treatment outcomes.
This technology is differentiated by its focus on depleting kynurenine, a metabolite that suppresses immune responses and promotes cancer cell survival. By targeting kynurenine, the technology addresses a critical pathway in cancer progression that is not directly targeted by many existing therapies. The use of kynureninase enzymes, particularly those that are PEGylated, allows for prolonged circulation and stability in the human body, enhancing their therapeutic potential. Additionally, the ability to combine these enzymes with other cancer treatments, such as checkpoint inhibitors, provides a synergistic approach that can lead to more effective cancer eradication. The engineering of enzymes to have high specificity and activity towards kynurenine further distinguishes this technology, offering a targeted and efficient method to disrupt cancer-promoting pathways.