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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.

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LYMPHOID NEOPLASIA

Potent antitumor activity of the anti-CD19 auristatin antibody drug conjugate hBU12-vcMMAE against rituximab-sensitive and -resistant lymphomas

Hans-Peter Gerber1, May Kung-Sutherland1, Ivan Stone1, Carol Morris-Tilden1, Jamie Miyamoto1, Renee McCormick1, Stephen C. Alley2, Nicole Okeley2, Brad Hayes3, Francisco J. Hernandez-Ilizaliturri4, Charlotte F. McDonagh5, Paul J. Carter5, Dennis Benjamin2, and Iqbal S. Grewal1

Departments of 1 Preclinical Therapeutics, 2 Chemistry, and 3 Analytical Biochemistry and Formulations, Seattle Genetics, Bothell, WA; 4 Departments of Medicine and Immunology, Roswell Park Cancer Institute, Buffalo, NY; and 5 Department of Antibody Engineering, Seattle Genetics, Bothell, WA

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 CD21high, 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 acute lymphoblastic leukemia.


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