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 Blood, 24 September 2009, Vol. 114, No. 13, pp. 2721-2729.
Prepublished online as a Blood First Edition Paper on July 24, 2009; DOI 10.1182/blood-2009-02-205500.

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LYMPHOID NEOPLASIA

Therapeutic potential of an anti-CD79b antibody–drug conjugate, anti–CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma

David Dornan1, Fiona Bennett2, Yvonne Chen1, Mark Dennis1, Dan Eaton1, Kristi Elkins1, Dorothy French1, Mary Ann T. Go1, Andrew Jack3, Jagath R. Junutula1, Hartmut Koeppen1, Jeffrey Lau1, Jacqueline McBride1, Andy Rawstron2,3, Xiaoyan Shi1, Nancy Yu1, Shang-Fan Yu1, Peng Yue1, Bing Zheng1, Allen Ebens1, and Andrew G. Polson1

1 Genentech Inc, South San Francisco, CA; 2 Haematological Malignancy Diagnostic Service, Leeds Teaching Hospitals, Leeds, United Kingdom; and 3 Department of Haematology, St James's Institute of Oncology, Leeds, United Kingdom

Here we describe the generation of an antibody–drug conjugate (ADC) consisting of a humanized anti-CD79b antibody that is conjugated to monomethylauristatin E (MMAE) through engineered cysteines (THIOMABs) by a protease cleavable linker. By using flow cytometry, we detected the surface expression of CD79b in almost all non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia patients, suggesting that anti–CD79b-vcMMAE could be widely used in these malignancies. By using NHL cell lines to simulate a patient population we discovered that a minimal cell-surface expression level of CD79b was required for in vitro activity. Within the subpopulation of cell lines above this minimal threshold, we found that sensitivity to free MMAE, mutation of cancer genes, and cell doubling time were poorly correlated with in vitro activity; however, the expression level of BCL-XL was correlated with reduced sensitivity to anti–CD79b-vcMMAE. This observation was supported by in vivo data showing that a Bcl-2 family inhibitor, ABT-263, strikingly enhanced the activity of anti–CD79b-vcMMAE. Furthermore, anti–CD79b-vcMMAE was significantly more effective than a standard-of-care regimen, R-CHOP (ie, rituximab with a single intravenous injection of 30 mg/kg cyclophosphamide, 2.475 mg/kg doxorubicin, 0.375 mg/kg vincristine, and oral dosing of 0.15 mg/kg prednisone once a day for 5 days), in 3 xenograft models of NHL. Together, these data suggest that anti–CD79b-vcMMAE could be broadly efficacious for the treatment of NHL.


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