LEAF-1401

LEAF-1401 is a novel nanoliposomal formulation of gamma-L-pentaglutamated pemetrexed, developed as an onco-immuno antimetabolite to disrupt dysregulated one-carbon metabolism in cancer and the immune system. By encapsulating the highly potent polyglutamated form of pemetrexed within liposomes, LEAF-1401 enables direct delivery of this active metabolite into tumor cells, bypassing resistance mechanisms such as downregulation of folylpolyglutamate synthase (FPGS) and folate transporters. Preclinical studies demonstrate that LEAF-1401 achieves up to 20-fold higher intratumoral exposure levels of pentaglutamated pemetrexed compared to conventional pemetrexed (Alimta), resulting in significantly enhanced inhibition of thymidylate synthase—a key enzyme in DNA synthesis—while maintaining an acceptable safety profile. The drug is designed to improve antitumor activity and overcome common antifolate resistance pathways[1][2][6].