Abstract 5330: Methioninase-loaded erythrocytes: a promising drug for L-methionine restriction therapy in cancer

Abstract

Abstract Several studies reported a complete dependence of different tumor cells on L-methionine (Met), an essential amino acid, for maintaining their high proliferation rate while normal cells keep their ability to grow on Met-deprived medium (Cavuoto and Fenech, 2012). Met restriction appearing as an important strategy for cancer treatment, different therapeutic approaches using either Met restricted regimens or Met-catabolizing enzymes were investigated. Phase I and II clinical trials associating dietary Met restriction with chemotherapy were conducted with cancer patients (Thivat et al., 2009; Durando et al, 2010). A 40% reduction of plasmatic methionine was achieved with a 1-day Met-free diet per month. Interesting long-duration of disease stabilization was observed in some patients. However this diet is extremely difficult to maintain. In order to obtain longer Met depletion in plasma, enzyme therapy using Methionine gamma-lyase (MGL), a pyridoxal-dependent enzyme that specifically degrades Met into alpha-ketobutyrate, ammonia and thiols, was explored. MGL enzyme isolated from Pseudomonas putida was selected as preferred candidate for the development of therapy. However, preclinical studies conducted in primates showed a very short half-life of the active form of MGL enzyme (2h) due to a rapid in vivo dissociation of the pyridoxal (PLP) cofactor (Yang et al., 2004). To overcome this problem of PLP-dissociation, we encapsulated the active MGL into erythrocytes, natural pool of PLP in the body and evaluated PK-PD parameters of product over a 5-day period in a mouse model. Once entrapped into erythrocytes, the MGL enzyme maintained more than 30% of its specific activity after 5 days in circulation. A 60-70% Met depletion was achieved 15 min post-injection and then depletion was stabilized at 40% over the 5 day-period of the study. In comparison, administration of the free MGL at similar doses led to a rapid loss of the active form in several hours. Met was totally deprived 15 min post-injection but plasmatic Met level returned to baseline by 24h. Increasing two-fold the concentration of free methioninase did not improved the in vivo Met depletion. In conclusion, we report that methioninase-loaded-erythrocytes can lower Met concentration in mouse plasma for at least 5 days and may be an innovative strategy to kill tumors by met-starvation. Citation Format: Fabien Gay, Julie Bes, Vanessa Bourgeaux, Yann Godfrin. Methioninase-loaded erythrocytes: a promising drug for L-methionine restriction therapy in cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5330. doi:10.1158/1538-7445.AM2015-5330