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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1594-1602.
Prepublished online as a Blood First Edition Paper on November 21, 2007; DOI 10.1182/blood-2007-03-082024.
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NEOPLASIA
Mediation of apoptosis by and antitumor activity of lumiliximab in chronic lymphocytic leukemia cells and CD23+ lymphoma cell lines
Nuzhat I. Pathan1,
Peter Chu1,
Kandasamy Hariharan1,
Carolyn Cheney2,
Arturo Molina1, and
John Byrd2
1 Departments of Oncology Cell Signaling and Tumor Biology, Biogen Idec, San Diego, CA; and
2 Division of Hematology/Oncology, Ohio State University, Columbus
Lumiliximab is a chimeric macaque-human monoclonal antibody to CD23, a protein expressed on virtually all chronic lymphocytic leukemia (CLL) cells. We examined the ability of lumiliximab to mediate apoptosis, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity against primary CLL cells and CD23-expressing B-cell lines. Our data suggest that lumiliximab kills CLL cells and CD23-expressing B cells predominantly by apoptosis, which occurs through the intrinsic pathway. Lumiliximab-induced apoptosis was accompanied by the down-regulation of antiapoptotic proteins Bcl-2, Bcl-XL, and XIAP, activation of Bax, and release of cytochrome c from the mitochondria. We also found that the addition of lumiliximab to rituximab or fludarabine results in synergistic cytotoxicity of primary CLL cells and CD23-expressing B-cell lines. We investigated the in vivo activity of lumiliximab in a human disseminated CD23+ B-cell lymphoma SCID mouse model and found greater antitumor activity with it than with control antibody. We also found that paralysis-free survival was greater with lumiliximab plus rituximab or fludarabine than with any of those agents alone. These results suggest that lumiliximab may be an effective treatment alone or in combination with rituximab or chemotherapy agents in CLL or other CD23-overexpressing B-cell malignancies.
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