Marked therapeutic efficacy of a novel polyethylene glycol-SN38 conjugate, EZN-2208, in xenograft models of B-cell non-Hodgkin's lymphoma.
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.
Sapra
Puja
P
Enzon Pharmaceuticals, Inc., 20 Kingsbridge Road, Piscataway, NJ 08854, USA. puja.sapra@enzon.com
Kraft
Patricia
P
Mehlig
Mary
M
Malaby
Jennifer
J
Zhao
Hong
H
Greenberger
Lee M
LM
Horak
Ivan D
ID
D000818:Animals; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000473:pathology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
C528970:EZN-2208; C106003:SN38-Glu; D011092:Polyethylene Glycols; D002166:Camptothecin