Modified kynureninase enzymes for cancer therapy

This invention describes modified kynureninase enzymes, particularly human enzymes, for degrading kynurenine. These enzymes can be used in compositions and methods for treating cancer by depleting kynurenine levels.

Background

Cancer immunotherapy has emerged as a promising approach to treating a wide range of malignancies. The goal of immunotherapy is to harness the power of the patient’s own immune system to recognize and eliminate cancer cells. However, tumors often develop mechanisms to evade immune surveillance, creating an immunosuppressive microenvironment that hinders the effectiveness of immunotherapy.

One such mechanism involves the overexpression of enzymes like indolamine-2,3-dioxygenase (IDO1 and IDO2) and tryptophan 2,3-dioxygenase (TDO) by cancer cells or associated immune cells. These enzymes catalyze the conversion of tryptophan to kynurenine (KYN), leading to local tryptophan depletion and kynurenine accumulation. High levels of kynurenine suppress the proliferation and function of T cells and natural killer (NK) cells, key players in anti-tumor immunity. Additionally, kynurenine promotes the differentiation of regulatory T cells (Tregs), which further dampen immune responses.

Current approaches to address this problem, such as using small molecule inhibitors of IDO1, have shown limited efficacy and are associated with drawbacks, including off-target effects and the inability to inhibit TDO or IDO2. Moreover, these inhibitors often fail to completely abrogate kynurenine production, leaving a residual immunosuppressive effect.

Technology description

This technology involves methods and compositions utilizing a modified kynureninase enzyme capable of degrading kynurenine. It includes the development of compositions and therapeutic methods aimed at treating cancer by depleting kynurenine levels using these proteins or corresponding nucleic acids. The technology also includes the use of the modified kynureninase enzyme in combination with other cancer therapies, such as anti-PD-1, anti-CTLA-4, or anti-PD-L1 antibodies.

This technology is differentiated from other cancer therapies because it specifically targets kynurenine, a metabolite of tryptophan that is produced by tumor cells to suppress the immune system. By depleting kynurenine levels, this technology aims to restore the ability of the immune system to fight cancer. Additionally, the use of enzymes for the depletion of kynurenine circumvents the problems associated with small molecule inhibitors of IDO isoforms and TDO, such as off-target effects and lack of inhibition for certain isoforms.

The technology also includes the development of modified kynureninase enzymes with improved catalytic activity and stability, as well as methods for conjugating the enzymes to other molecules, such as polyethylene glycol (PEG), to increase their serum persistence.