Engineered enzymes for enhanced kynurenine degradation in cancer therapy

The technology describes a modified human kynureninase enzyme with enhanced catalytic efficiency for degrading kynurenine, achieved through specific amino acid substitutions. This enzyme, used in therapeutic applications, reduces kynurenine levels to mitigate tumor-mediated immune suppression and promote anti-tumor immune responses.

Background

Cancer cells often employ mechanisms to evade the immune system, one of which involves the overexpression of enzymes like indolamine-2,3-dioxygenase (IDO1 and IDO2) and tryptophan 2,3-dioxygenase (TDO). These enzymes catalyze the conversion of tryptophan into kynurenine, which has immunosuppressive effects, aiding tumor survival. Elevated kynurenine levels in the tumor microenvironment and in the serum of cancer patients can inhibit T-cell growth and induce apoptosis, thereby preventing effective immune responses against tumors.

Existing therapeutic approaches, such as small molecule inhibitors targeting IDO1, have shown promise but are limited by their inability to inhibit TDO and potential off-target effects. Furthermore, bacterial enzymes capable of degrading kynurenine have been explored, but their non-human origin poses risks of adverse immune responses. There is a need for human-compatible enzymes with enhanced catalytic efficiency to degrade kynurenine effectively, to restore immune surveillance and improve cancer treatment outcomes.

Technology description

The technology centers on a modified human kynureninase enzyme designed to degrade kynurenine with enhanced catalytic efficiency. This enzyme has been engineered through key amino acid substitutions, which significantly improve its activity compared to the wild-type enzyme. The invention also covers therapeutic applications, particularly in cancer treatment, where these modified enzymes (or their corresponding nucleic acids) are administered to reduce kynurenine concentrations. This reduction helps mitigate tumor-mediated immune suppression and promotes anti-tumor immune responses. Additionally, the invention includes various formulations and delivery methods, such as PEGylation to increase serum persistence and potential integration into T cells with chimeric antigen receptors (CARs) for targeted cancer therapy.

What differentiates this technology is its ability to address the limitations of existing cancer treatments that target the kynurenine pathway. This modified kynureninase enzyme, with its enhanced catalytic efficiency and human origin, offers a more effective and safer alternative by directly degrading kynurenine. This approach not only avoids the adverse immune responses associated with non-human enzymes but also provides a robust method to lower kynurenine levels, enhancing the immune system's ability to fight tumors. The inclusion of various delivery methods, such as PEGylation and CAR-T cell integration, further enhances the therapeutic potential and versatility of this technology in cancer treatment.

Benefits

Enhanced catalytic efficiency compared to wild-type human enzyme.
Therapeutic applications for cancer treatment by depleting kynurenine levels.
Mitigation of tumor-mediated immune suppression.
Promotion of anti-tumor immune responses.
Formulations and delivery methods, including PEGylation for increased serum persistence.
Potential integration into T cells with chimeric antigen receptors (CARs) for targeted cancer therapy.