Reference Detail

Ref Type

PMID

Authors

Yumi Yokoyama, Michael Nedelcovych, Robert Wild

Title

DRP-104, a novel broad acting glutamine antagonist, induces distinctive immune modulation mechanisms and synergistic efficacy in combination with immune checkpoint blockade

Journal	Vol	Issue	Date	Pages	Journal Short Title
			2019

URL

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833189/

Abstract Text

Background: Glutamine is an essential amino acid for rapidly proliferating cancer cells, thus depriving the same fuel from immune cells and contributing to tumor immune evasion. DRP-104 was designed as a novel prodrug of the broad acting glutamine antagonist 6-Diazo-5-oxo-L-norleucine (DON). DRP-104 is inert in its prodrug form, affords high levels of plasma and gastro-intestinal (GI) tissue stability; has high tumor cell permeability and preferential tumor versus plasma/GI tissue distribution for DON. Here we sought to (1) compare immunological modulation of DRP-104 to anti-PD-1Ab, and (2) evaluate the combination effect of DRP-104 with PD-1/PD-L1 checkpoint inhibitors. Methods: Immunomodulatory effects of DRP-104 as a single agent and combination with anti-PD-1Ab was evaluated in the CT26 mouse colon carcinoma model by flow cytometry and Luminex assay. In vivo anti-tumor efficacy of combination with anti-PD-1/PD-L1Ab was evaluated in CT26 and H22 hepatocellular carcinoma models. Results: DRP-104 treatment showed broad immune cell modulation effects including increased T, NK, and macrophages; while anti-PD-1Ab affected mainly CD8+T cells. Cytokine modulation in tumor and plasma revealed that DRP-104 decreased pro-tumorigenic cytokines such as VEGF and KC(IL-8) while anti-PD-1Ab showed either no change or slight increase in these cytokines. CT26 bearing mice treated with anti-PD-1Ab alone, DRP-104, and the combination showed tumor growth inhibition at day 12 of 48%, 90%, and 94%, respectively. Median survival days were 31.5, 36, and 56 days, respectively (vehicle; 17.5 days). Notably 9 mice treated with combination of anti-PD-1 with DRP-104 were tumor free at end of the experiment (day 77) and 100% of these mice rejected a CT26 tumor re-challenge. In the H22 model, mice were treated with either anti-PD-L1 Ab, DRP-104, or combination. While anti-PD-L1Ab did not show tumor growth inhibition in this model, DRP-104 significantly inhibited tumor growth and the combination further enhanced efficacy, illustrated by extended survival for both DRP-104 alone (50 days) and combination (96 days) treatment groups compared to vehicle (33days) and anti-PD-L1 alone (33days). Combination treatment also resulted in long term durable cures in 50% of the mice. Conclusions: DRP-104 treatment results in dramatic remodeling of the tumor micro environment, leading to enhanced function of multiple immune cells distinct from activities obtained by anti-PD-1 Ab. Combination therapy of DRP-104 with anti-PD-1/PD-L1 achieved significantly enhanced anti-tumor efficacy including long-term durable cures even in checkpoint inhibitor resistant models. This unique and non-overlapping mechanism of action supports clinical development of DRP-104 alone and in combination with PD-1/PD-L-1 checkpoint inhibitors.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
DRP-104	DRP-104	0	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
DRP-104		DRP 104\|DRP104\|Sirpiglenastat		Sirpiglenastat (DRP-104) is the prodrug form of glutamine antagonist, which potentially modulates immune response and inhibits tumor growth (J Immunother Cancer. 2019; 7(Suppl 1): 282, Abs nr: P497).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References