Transforming Cancer Treatment by Targeting Adenosine-Mediated Immunosuppression

Introduction

Adenosine and methylthioadenosine (MTA) are critical molecules involved in cellular processes, but in cancer, they play a different role—contributing to immune evasion by suppressing the body’s natural immune response against tumors. Tumors exploit these molecules to create a hostile environment that weakens the immune system, making it more difficult for therapies like immunotherapy to work effectively. Our patented enzyme-mediated depletion technology offers an innovative way to disrupt this protective barrier by depleting adenosine and/or methylthioadenosine, allowing the immune system to regain its ability to fight cancer cells and enhancing the efficacy of cancer treatments.

The Challenge of Immunosuppression in Cancer

Cancer immunotherapy has made significant advances in recent years, with treatments like checkpoint inhibitors and CAR-T therapies offering new hope for patients. However, a major obstacle remains: the immunosuppressive microenvironment created by tumors. Adenosine, in particular, accumulates in the tumor microenvironment and actively suppresses immune cells, such as T cells and natural killer (NK) cells, which are essential for combating cancer. This immunosuppression severely limits the effectiveness of existing therapies, creating an urgent need for methods to neutralize these barriers.

For pharmaceutical companies and researchers, the ability to modulate the tumor microenvironment to overcome adenosine-mediated immunosuppression is key to advancing cancer treatment and improving patient outcomes.

An Innovative Approach: Enzyme-Mediated Depletion

Our patented technology introduces an enzyme-based approach that targets and depletes adenosine and/or methylthioadenosine in the tumor microenvironment. By breaking down these immunosuppressive molecules, this method restores the immune system’s ability to recognize and attack cancer cells. It acts as a complement to existing immunotherapies, enhancing their potency and increasing the likelihood of a sustained immune response against the tumor.

This approach has broad potential, not just in oncology but in immune-related diseases where adenosine and MTA accumulation suppress immune function. It can be applied in combination with other therapies, such as immune checkpoint inhibitors or chemotherapy, to provide a more comprehensive treatment strategy.

Key Benefits

Overcoming Tumor Immunosuppression: Depletes adenosine and MTA, reducing immunosuppressive barriers and enabling a more effective immune response.
Enhanced Immunotherapy: Boosts the efficacy of existing immunotherapies, such as checkpoint inhibitors and CAR-T cells.
Broad Applications: Useful in cancer treatment and other immune-related conditions where adenosine accumulation is a problem.
Synergistic Potential: Can be combined with a variety of cancer treatments for more comprehensive, multi-targeted strategies.

A New Avenue for Cancer Immunotherapy

Licensing this enzyme-mediated depletion technology offers pharmaceutical companies the opportunity to pioneer a new class of treatments that target tumor immunosuppression. By restoring immune function in the tumor microenvironment, this technology paves the way for more effective cancer therapies and better outcomes for patients.

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Abstract
Claims

Methods and compositions related to the engineering of a protein with MTA/ADO-degrading enzyme activity are described. For example, in certain aspects there may be disclosed an MTase capable of degrading MTA/ADO. Furthermore, certain aspects of the invention provide compositions and methods for the treatment of cancer or SCID with an MTase using the disclosed proteins or nucleic acids.

What is claimed is:

1. A composition for treating a methylthioadenosine phosphorylase-deficient cancer comprising:

an enzyme capable of phosphorolysis of methylthioadenosine into methylthioribose-phosphate and adenine coupled to

a compound capable of increasing a serum half-life of the enzyme;

wherein the enzyme comprises a sequence having at least 90% identity to SEQ ID NO: 1, and

wherein the compound capable of increasing a serum half-life of the enzyme is a polymer that increases a hydrodynamic radius of the enzyme.

2. The composition of claim 1, wherein the compound capable of increasing a serum half-life of the enzyme is polyethylene glycol.

3. The composition of claim 2, wherein the polyethylene glycol is coupled to the enzyme via conjugation to one or more lysine residues of the enzyme.

4. A method of treating a patient having a tumor comprising administering to the patient an effective amount of a methylthioadenosine phosphorylase comprising a sequence having at least 90% identity to SEQ ID NO: 1.

5. The method of claim 4, wherein the methylthioadenosine phosphorylase is coupled to a compound capable of increasing a serum half-life of the methylthioadenosine phosphorylase.

6. The method of claim 5, wherein the methylthioadenosine phosphorylase is conjugated to polyethylene glycol.

7. The method of claim 6, further comprising administering a second anti-cancer therapy to the patient.

8. The method of claim 7, wherein the second anti-cancer therapy is an immune checkpoint inhibitor.

9. The method of claim 8, wherein the immune checkpoint inhibitor is an anti-PD1 antibody, an anti-CTLA4 antibody, or an anti-PD-L1 antibody.

10. The method of claim 5, wherein the tumor comprises:

a deletion of a methylthioadenosine phosphorylase gene,

an increased level of methylthioadenosine relative to a reference level, or

a decreased level of methylthioadenosine phosphorylase relative to a reference level.

11. The method of claim 10, wherein the deletion of a methylthioadenosine phosphorylase gene comprises a homologous genetic deletion at chromosome band 9p21.

12. The method of claim 10, wherein the reference level is a level in a healthy tissue of the patient.

13. The method of claim 10, wherein the reference level is a level in a healthy individual.

14. A method of treating a patient having a tumor comprising:

a) determining that the tumor comprises a homologous genetic deletion at chromosome 9p21 of a methylthioadenosine phosphorylase gene; and

b) administering an enzyme capable of phosphorolysis of methylthioadenosine into methylthioribose-phosphate and adenine,

wherein the enzyme comprises a sequence having at least 90% identity to SEQ ID NO: 1.

15. The method of claim 14, wherein the enzyme is conjugated to polyethylene glycol via one or more lysine residues of the enzyme.

Title

Enzyme-mediated depletion of adenosine and/or methylthioadenosine

Inventor(s)

Everett Stone, Donjeta GJUKA

Assignee(s)

University of Texas System

Patent #

11118167

Patent Date

July 14, 2021