Improved Human Methylthioadenosine/Adenosine (MTA/ADO) Depleting Enzyme Variants for Cancer Therapy

The technology involves engineered polypeptides (and their compositions, nucleic acids, expression vectors, host cells and methods) that degrade methylthioadenosine and adenosine to treat cancers with MTAP gene deletions. These polypeptides are conjugated with polymers like PEG to enhance their stability and reduce immunogenicity, improving immune response in the tumor microenvironment.

Background

Gene deletions and mutations in cancer cells often lead to the accumulation of certain metabolites that can suppress the immune system and promote tumor growth. One such metabolite is methylthioadenosine (MTA), which accumulates in the absence of functional methylthioadenosine phosphorylase (MTAP) enzyme due to genetic deletions or mutations.

The buildup of MTA has been linked to immunosuppressive effects, such as inhibiting the proliferation and activation of T-cells, which are crucial for the immune system's ability to target and destroy cancer cells. This immunosuppression can contribute to the tumor's ability to evade immune surveillance and resist immune-based therapies.

Existing approaches to counteract this involve targeting the metabolic pathways or using immune checkpoint inhibitors, but these can be limited by the tumor's adaptive resistance mechanisms and the complexity of the tumor microenvironment. Therefore, there is a need for strategies that can effectively degrade MTA and restore immune function to enhance the efficacy of cancer treatments.

Technology description

The technology involves the development of conjugated polypeptides with enzymatic activity specifically designed to degrade methylthioadenosine and adenosine. These polypeptides are engineered to enhance conjugation while maintaining their catalytic function, and they can be linked with polymers like polyethylene glycol (PEG) to improve their serum half-life and reduce immunogenicity. The technology also encompasses nucleic acids, expression vectors, host cells and methods related to these polypeptides.

The polypeptides are intended for use in pharmaceutical formulations aimed at treating cancers, particularly those with MTAP gene deletions or reduced MTAP activity. By reducing MTA levels in the tumor microenvironment, they help alleviate immunosuppression and promote immune cell infiltration.

This technology is differentiated by its focus on addressing the immunosuppressive environment often associated with certain cancers. The conjugated polypeptides are specifically designed to target and degrade MTA and ADO, which are known to contribute to tumor growth and immune evasion. By enhancing the serum half-life and reducing the immunogenicity of these polypeptides through PEGylation, the technology ensures a more effective and sustained therapeutic action.

This approach not only targets the tumor directly but also modulates the immune response, making it a promising strategy for cancers with specific genetic deletions or reduced enzyme activity. The integration of nucleic acids and expression systems further supports the tailored production and application of these therapeutic agents.

Benefits

Reduces MTA levels in the tumor microenvironment to alleviate immunosuppression
Potentially treats cancers with MTAP gene deletions or reduced MTAP activity
Enhances serum half-life and reduces protein immunogenicity through PEG conjugation
Enhances immune cell infiltration into tumors
Provides methods for pharmaceutical formulations using engineered polypeptides
Offers a novel approach for cancer therapy with low immunogenicity and improved serum stability