Technology: Arginine Modulators

Recent literature (review, ref 1) has highlighted a conspicuous absence of small molecule drugs with application to cancer therapy in the new era of immuno-oncology[1]. Modulating the immune system through a small-molecule approach offers several unique advantages that are complementary to, and potentially synergistic with, biologic modalities. The review highlighted immuno-oncology pathways and mechanisms that can be best or solely targeted by small-molecule medicines. Agents aimed at these mechanisms — modulation of the immune response — are poised to significantly extend the scope of immuno-oncology applications and enhance the opportunities for combination with tumour-targeted agents and biologic immunotherapies.

The review highlighted a key mechanism of cancer escape resulting from the depletion of the amino acid arginine in the tumor microenvironment. Depletion of intracellular and extracellular arginine results in impaired T-cell receptor signaling resulting in an impaired immune response to the growing cancer. Small molecule drugs that increase the availability of arginine in the tumor microenvironment therefore have future utility and great promise both as single agents and in combination with other cancer medicines.

In late 2016, an exclusive and world-wide material transfer agreement with the Baker IDI to access arginine modulating compounds in the field of cancer and specifically immuno-oncology was signed. Imugene has filed a patent protecting the use of the compound set in the field of oncology and treatment of proliferative disorders such as cancer.

Imugene’s arginine modulators augment the transport of L-arginine into various human cells by 30% or more, resulting in vasodilation and lowering of blood pressure in animal models of cardiovascular disease. Most recently the Baker extended these observations by performing chronic infusions of the lead molecule in hypertensive mice via osmotic minipumps at a dose of 30mg/kg/day. The mean arterial blood pressure (MAP) was lowered particularly during periods of activity (ie night time). The lead molecule was well tolerated over the 5-7 day infusion period. Importantly, increased levels of NO metabolites (nitrate and nitrite) were measured in the plasma of these mice, indicating increased levels of arginine for conversion to NO are apparent.

The field of tumor immunology is focused on developing agents that activate the body's own immune system to attack and kill tumors. Imugene's new preclinical program in tumor immunology will be focused on developing modulators of arginine bioavailability in the tumor microenvironment where arginine is often depleted. By increasing the availability of arginine in and around the tumor, it may be possible to restore the tumor killing activity of cytotoxic T cells by preventing the depletion of arginine. A recent publication in the prestigious journal Cell supports our hypothesis where Swiss researcher’s found that T cells with increased arginine levels display improved anti-tumor activity[2].

In 2H, 2017; Imugene tested the lead compound in a panel of 12 different cancer syngeneic mouse models of the most prevalent cancers, with significant activity in a melanoma cancer model.

Imugene is applying its core expertise in tumor immunology to rapidly advance selective small-molecule arginine modulators into the clinic to develop a first-in-class immuno-oncology therapy for cancer patients.

[1] Hoos, A. etal. Big opportunities for small molecules in immune-oncology, Nat Rev Drug Discov. 2015;14(9):603-22

[2] Geiger, R etal. L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity, Cell.2016;167(3):829-842