The HB22.7 Anti-CD22 monoclonal antibody enhances bortezomib-mediated lymphomacidal activity in a sequence dependent manner

Journal of Hematology & Oncology

Joseph M Tuscano³  Robert T O'Donnell³  Yunpeng Ma²  Christopher M Mahaffey²  Hayes McKnight²  Eric Churchill¹  Shiloh M Martin² 

[1] Millennium Pharmaceuticals Inc., (40 Landsdown St Cambridge MA (02139) USA;Department of Internal Medicine, Division of Hematology and Oncology, University of California, Davis Cancer Center, (4501 X Street), Sacramento, CA (95817), USA;Northern California Veterans Administration Healthcare System, (10535 Hospital Way), Mather, CA (95655), USA

关键词: mantle cell lymphoma;    apoptosis;    reactive oxygen species;    Non-Hodgkin's lymphoma;    proteasome inhibition;    Velcade;    bortezomib;    CD22;    HB22.7;   

Others  :  826113
DOI  :  10.1186/1756-8722-4-49

 received in 2011-11-01, accepted in 2011-12-01,  发布年份 2011

【 摘 要 】

Most non-Hodgkin's lymphomas (NHL) initially respond to chemotherapy, but relapse is common and treatment is often limited by chemotherapy-related toxicity. Bortezomib, is a highly selective proteasome inhibitor with anti-NHL activity; it is currently FDA approved for second-line treatment of mantle cell lymphoma (MCL). Bortezomib exerts its activity in part through the generation of reactive oxygen species (ROS) and also by the induction of apoptosis.

We previously validated CD22 as a potential target in treating NHL and have shown that the anti-CD22 ligand blocking antibody, HB22.7, has significant independent lymphomacidal properties in NHL xenograft models. We sought to determine whether or not these agents would work synergistically to enhance cytotoxicity. Our results indicate that treatment of NHL cell lines with HB22.7 six hours prior to bortezomib significantly diminished cell viability. These effects were not seen when the agents were administered alone or when bortezomib was administered prior to HB22.7. Additionally, HB22.7 treatment prior to bortezomib increased apoptosis in part through enhanced ROS generation. Finally, in a mouse xenograft model, administration of HB22.7 followed 24 hours later by bortezomib resulted in 23% smaller tumor volumes and 20% enhanced survival compared to treatment with the reverse sequence. Despite the increased efficacy of HB22.7 treatment followed by bortezomib, there was no corresponding decrease in peripheral blood cell counts, indicating no increase in toxicity. Our results suggest that pre-treatment with HB22.7 increases bortezomib cytotoxicity, in part through increased reactive oxygen species and apoptosis, and that this sequential treatment combination has robust efficacy in vivo.

【 授权许可】

   
2011 Martin et al; licensee BioMed Central Ltd.

【 图 表 】

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