Arginine-depleting pegylated arginine deiminase

Class

enzyme therapy

Arginine deiminase is a bacterial enzyme that breaks down the amino acid arginine into citrulline and ammonia, rather than acting on a human receptor or pathway. As a therapeutic, it is chemically modified with polyethylene glycol (PEGylation) to reduce immune recognition and prolong its circulation in blood, where it lowers systemic arginine levels. The biological rationale rests on a metabolic vulnerability found in some tumors: healthy human cells can regenerate arginine internally from citrulline using the enzyme argininosuccinate synthetase 1 (ASS1), part of the urea cycle. Certain cancers, however, silence the gene encoding ASS1, making them unable to perform this conversion. These tumors become dependent on arginine absorbed from the bloodstream, a state called arginine auxotrophy. By depleting circulating arginine, this enzyme therapy selectively starves ASS1-deficient tumor cells of an amino acid essential for protein synthesis and growth, while normal tissues largely compensate by synthesizing their own supply from citrulline. This mechanism has been explored across cancers known to frequently lose ASS1 expression, including certain mesotheliomas, liver cancers, sarcomas, and melanomas. It represents a metabolic rather than a signaling-based approach to cancer treatment, exploiting a biochemical difference between tumor and normal cell metabolism.