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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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Submitted January 10, 2007
Accepted March 5, 2007
Antibody-drug conjugates targeted to CD79 for the treatment of non-Hodgkin's lymphoma
Andrew G. Polson*, Shang-Fan Yu, Kristi Elkins, Bing Zheng, Suzanna Clark, Gladys S. Ingle, Dionysos S. Slaga, Lynne Giere, Changchun Du, Christine Tan, Jo-Anne Hongo, Alvin Gogineni, Mary J. Cole, Richard Vandlen, Jean-Philippe Stephan, Judy Young, Wesley Chang, Suzie J. Scales, Sarajane Ross, Dan Eaton, and Allen Ebens
Department of Translational Oncology, Genentech, South San Francisco, CA, United States
Department of Molecular Biology, Genentech, South San Francisco, CA, United States
Department of Antibody Technology, Genentech, South San Francisco, CA, United States
Department of Tumor Biology and Angiogenesis, Genentech, South San Francisco, CA, United States
Department of Protein Chemistry, Genentech, South San Francisco, CA, United States
Department of Assay Automation Technology, Genentech, South San Francisco, CA, United States
Department of Pathology, Genentech, South San Francisco, CA, United States
* Corresponding author; email: polson{at}gene.com.
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 (BCR), and are attractive targets for the use of ADCs since they are B-cell specific, expressed in non-Hodgkin's lymphomas (NHLs), and 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 NHL cell lines in vitro. Further, these two ADCs are equally effective at low doses in xenograft models of follicular, mantle cell, and Burkitt's 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 down-regulated surface BCR and were trafficked to the lysosomal-like 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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December 1, 2007;
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[Abstract]
[Full Text]
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