L.E.A.F. Pharmaceuticals currently has several new chemical entities in development, targeting solid tumors.
Premise of L.E.A.F. Pipeline
Antifolates polyglutamates are far more potent than the parent monoglutamate forms
Resistance to antifolates is in part due to overexpression of Gamma Glutamyl Hydrolase (GGH), an intracellular enzyme that has been linked to poor prognosis in cancer patients as well as to resistance to antifolate based cancer treatments.
L.E.A.F. products are designed to bypass the need for polyglutamation by folylpolyglutamate synthase (FPGS) and to minimize/overcome the influence of GGH in tumor resistance mechanisms to drug treatment.
In vitro: L.E.A.F. liposomal polyglutamated pemetrexed analogs are more potent than pemetrexed in various tumor cell lines but preserve normal cells following exposure over 48 hours
*Relative Potency as defined by the ratio of IC50 of pemetrexed over the IC50 of respective liposomal polyglutamated pemetrexed analog
In vivo: Mouse Maximum Tolerated Dose (MTD) studies of LEAF-1401 and
LEAF-1701 show minimal myelosuppression and gastrointestinal (GI) toxicity at MTD
LEAF-1401 reduced metastatic tumor burden on A549 lung cancer orthotopic models
*Tumor burden measured as Bioluminescense Image (BLI) Signal intesnity; pemetrexed dose equivalent to approved dose of 500mg/m2
LEAF-1401 and LEAF-1701 were both superior to pemetrexed in CT26 colorectal models