MedKoo product information:

  EZN-2208 (Pegylated SN-38)

EZN-2208 is  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. (source: Haematologica. 2009 October; 94(10): 1456–1459. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754965).

EZN-2208 was about 100-fold more potent than CPT-11 in vitro, by inducing apoptosis/necrosis and p53 expression and by reducing hypoxia-inducible factor (HIF)-1α/HIF-2α expression. EZN-2208 gave superior antitumor effects compared with CPT-11 in neuroblastoma xenografts. EZN-2208 treatment always resulted in lack of tumor detection at the end of trials whereas only small therapeutic effects were observed with CPT-11, as assessed by luciferase assay or tumor size, or even by staining histologic sections of tumors with antibodies recognizing neuroblastoma cells and cell proliferation. In a neuroblastoma model resistant to doxorubicin, cisplatin, vincristine, fenretinide, and topotecan, EZN-2208 induced 100% curability. It also blocked tumor relapse after topotecan-vincristine-doxorubicin combined treatment. Mechanistic experiments showed statistically significantly enhanced terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Histone H2ax staining as well as decreased vascular endothelial growth factor, CD31, matrix metalloproteinase (MMP)-2, and MMP-9 expression in tumors removed from EZN-2208-treated mice and radiating vessels invading the tumor implanted onto the chorioallantoic membranes. (source: Clin Cancer Res. 2010 Oct 1;16(19):4809-21. Epub 2010 Aug 11.).

Current developer:   Enzon Pharmaceuticals.

1: Sapra P, Kraft P, Pastorino F, Ribatti D, Dumble M, Mehlig M, Wang M, Ponzoni M, Greenberger LM, Horak ID. Potent and sustained inhibition of HIF-1α and downstream genes by a polyethyleneglycol-SN38 conjugate, EZN-2208, results in anti-angiogenic effects. Angiogenesis. 2011 Sep;14(3):245-53. Epub 2011 Mar 31. PubMed PMID: 21452059; PubMed Central PMCID: PMC3155047.

2: Pastorino F, Loi M, Sapra P, Becherini P, Cilli M, Emionite L, Ribatti D, Greenberger LM, Horak ID, Ponzoni M. Tumor regression and curability of preclinical neuroblastoma models by PEGylated SN38 (EZN-2208), a novel topoisomerase I inhibitor. Clin Cancer Res. 2010 Oct 1;16(19):4809-21. Epub 2010 Aug 11. PubMed PMID: 20702613.

3: Sapra P, Kraft P, Mehlig M, Malaby J, Zhao H, Greenberger LM, Horak ID. Marked therapeutic efficacy of a novel polyethylene glycol-SN38 conjugate, EZN-2208, in xenograft models of B-cell non-Hodgkin's lymphoma. Haematologica. 2009 Oct;94(10):1456-9. PubMed PMID: 19794091; PubMed Central PMCID: PMC2754965.

4: Sapra P, Zhao H, Mehlig M, Malaby J, Kraft P, Longley C, Greenberger LM, Horak ID. Novel delivery of SN38 markedly inhibits tumor growth in xenografts, including a camptothecin-11-refractory model. Clin Cancer Res. 2008 Mar 15;14(6):1888-96. PubMed PMID: 18347192.