Blood, 15 July 2007, Vol. 110, No. 2, pp. 616-623.
Prepublished online as a Blood First Edition Paper on March 20, 2007; DOI 10.1182/blood-2007-01-066704.
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NEOPLASIA
Antibody-drug conjugates targeted to CD79 for the treatment of non-Hodgkin lymphoma
Andrew G. Polson1,
Shang-Fan Yu1,
Kristi Elkins1,
Bing Zheng1,
Suzanna Clark1,
Gladys S. Ingle2,
Dionysos S. Slaga1,
Lynne Giere1,
Changchun Du1,
Christine Tan3,
Jo-Anne Hongo3,
Alvin Gogineni4,
Mary J. Cole4,
Richard Vandlen5,
Jean-Philippe Stephan6,
Judy Young6,
Wesley Chang7,
Suzie J. Scales2,
Sarajane Ross1,
Dan Eaton5, and
Allen Ebens1
Departments of1 Translational Oncology
2 Molecular Biology
3 Antibody Technology
4 Tumor Biology and Angiogenesis
5 Protein Chemistry
6 Assay Automation Technology, and
7 Pathology, Genentech, South San Francisco, CA
Targeting cytotoxic drugs to cancer cells using antibody–drug conjugates (ADCs), particularly those with stable linkers between the drug and the antibody, could be an effective cancer treatment with low toxicity. However, for stable-linker ADCs to be effective, they must be internalized and degraded, limiting potential targets to surface antigens that are trafficked to lysosomes. CD79a and CD79b comprise the hetrodimeric signaling component of the B-cell receptor, and are attractive targets for the use of ADCs because they are B-cell–specific, expressed in non-Hodgkin lymphomas (NHL), and are trafficked to a lysosomal-like compartment as part of antigen presentation. We show here that the stable-linker ADCs anti-CD79b-MCC-DM1 and anti-CD79b-MC-MMAF are capable of target-dependent killing of nonHodgkin lymphoma cell lines in vitro. Further, these 2 ADCs are equally effective as low doses in xenograft models of follicular, mantle cell, and Burkitt lymphomas, even though several of these cell lines express relatively low levels of CD79b in vivo. In addition, we demonstrate that anti-CD79b ADCs were more effective than anti-CD79a ADCs and that, as hypothesized, anti-CD79b antibodies downregulated surface B-cell receptor and were trafficked to the lysosomal-like major histocompatibility complex class II–positive compartment MIIC. These results suggest that anti-CD79b-MCC-DM1 and anti-CD79b-MC-MMAF are promising therapeutics for the treatment of NHL.
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