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

• Published in: Haematologica (Roma) 2009-10, Vol.94 (10), p.1456-1459
• Main Authors: Sapra, Puja, Kraft, Patricia, Mehlig, Mary, Malaby, Jennifer, Zhao, Hong, Greenberger, Lee M, Horak, Ivan D
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Brief Reports; Burkitt Lymphoma - drug therapy; Burkitt Lymphoma - pathology; Camptothecin - analogs & derivatives; Camptothecin - chemistry; Camptothecin - therapeutic use; Cell Line, Tumor; Female; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, B-Cell - drug therapy; Lymphoma, B-Cell - pathology; Medical sciences; Mice; Mice, SCID; Polyethylene Glycols - chemistry; Polyethylene Glycols - therapeutic use; Xenograft Model Antitumor Assays - methods
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2009.008276

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 IC 50 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.