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Marked therapeutic efficacy of a novel polyethylene glycol-SN38 conjugate, EZN-2208, in xenograft models of B-cell non-Hodgkin’s lymphoma

Enzon Pharmaceuticals, Inc., Piscataway, NJ, USA

Correspondence: Puja Sapra, Enzon Pharmaceuticals, Inc., 20 Kingsbridge Road, Piscataway, NJ 08854, USA. E-mail:puja.sapra{at}enzon.com The online version of this article contains a supplementary appendix.

Examination of the clinical utility of SN38 (10-hydroxy-7-ethyl-camptothecin), the active metabolite of CPT-11, has not been possible to date due to poor solubility of SN38. Here we evaluated the activity of EZN-2208, a water-soluble polyethyleneglycol-SN38 conjugate, in pre-clinical models of Burkitt’s non-Hodgkin’s lymphoma (NHL) (Raji and Daudi), and follicular NHL (DoHH2). In vitro, the IC₅₀ of EZN-2208 ranged from 3–24 nM, which was 30- to 45-fold lower than CPT-11 or 2.5- to 3.5-fold higher than SN38. In both an early-disease Raji model and an advanced-disease Daudi model, treatment with multiple doses of EZN-2208 resulted in 90% and 100% cures of animals, respectively (cure defined as no sign of tumors by gross observations at the termination of study). The activity of EZN-2208 was dramatically superior to that of CPT-11 in all three models. The excellent therapeutic efficacy of EZN-2208 in several B-cell NHL xenograft models merits its evaluation in the clinic for lymphoid malignancies.

Key words: SN38, polyethylene glycol, drug conjugate, B-cell non-Hodgkin’s lymphoma, CPT-11, in vivo.