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Blood, 30 April 2009, Vol. 113, No. 18, pp. 4352-4361. Prepublished online as a Blood First Edition Paper on January 15, 2009; DOI 10.1182/blood-2008-09-179143. This Article Full Text (PDF) Supplemental Table and Figure All Versions of this Article: blood-2008-09-179143v1 113/18/4352    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gerber, H.-P. Articles by Grewal, I. S. Search for Related Content PubMed PubMed Citation Articles by Gerber, H.-P. Articles by Grewal, I. S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 18, 2008 Accepted December 31, 2008 Potent antitumor activity of the anti-CD19 auristatin antibody-drug conjugate hBU12-vcMMAE against rituximab sensitive and resistant lymphomas Hans-Peter Gerber*, May Kung-Sutherland, Ivan Stone, Caroll Morris-Tilden, Jamie Miyamoto, Renee McCormick, Stephen C. Alley, Nicole Okeley, Brad Hayes, Francisco J. Hernandez-Ilizaliturri, Charlotte F. McDonagh, Paul J. Carter, Dennis Benjamin, and Iqbal S. Grewal Department of Preclinical Therapeutics, Seattle Genetics, Inc., Bothell, WA, United States Department of Chemistry, Seattle Genetics, Inc., Bothell, WA, United States Department of Analytical Biochemistry and Formulations, Seattle Genetics, Inc., Bothell, WA, United States Departments of Medicine and Immunology, Roswell Park Cancer Center, Buffalo, NY, United States Antibody Engineering, Seattle Genetics, Inc., Cambridge, MA, United States VLST, Inc., Seattle, WA, United States * Corresponding author; email: hgerber{at}seagen.com. Despite major advances in the treatment of non-Hodgkin lymphoma (NHL), including the use of chemotherapeutic agents and the anti-CD20 antibody rituximab, the majority of patients eventually relapse and salvage treatments with non-cross-resistant compounds are needed to further improve patient survival. Here, we evaluated the antitumor effects of the microtubule destabilizing agent monomethyl auristatin E (MMAE) conjugated to the humanized anti-CD19 antibody hBU12 via a protease sensitive valine-citrulline (vc) dipeptide linker. hBU12-vcMMAE induced potent tumor cell killing against rituximab sensitive and resistant NHL cell lines. CD19 can form heterodimers with CD21 and high levels of CD21 were reported to interfere negatively with the activity of CD19 targeted therapeutics. However, we observed comparable internalization, intracellular trafficking and drug release in CD21low and high, rituximab sensitive and refractory lymphomas treated with hBU12-vcMMAE. Furthermore, high rates of durable regressions in mice implanted with these tumors were observed, suggesting that both rituximab resistance and CD21 expression levels do not impact on the activity of hBU12-vcMMAE. Combined, our data suggest that hBU12-vcMMAE may represent a promising addition to the treatment options for rituximab refractory NHL and other hematologic malignancies, including ALL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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