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 Blood, 15 October 2006, Vol. 108, No. 8, pp. 2648-2654.
Prepublished online as a Blood First Edition Paper on July 6, 2006; DOI 10.1182/blood-2006-04-020057.

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IMMUNOBIOLOGY

Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab

Julie A. Bowles, Siao-Yi Wang, Brian K. Link, Barrett Allan, Gregory Beuerlein, Mary-Ann Campbell, David Marquis, Brian Ondek, James E. Wooldridge, Brian J. Smith, James B. Breitmeyer, and George J. Weiner

From the Holden Comprehensive Cancer Center, the Department of Internal Medicine, the Graduate Program in Immunology, and the Department of Biostatistics, University of Iowa, Iowa City; and Applied Molecular Evolution, San Diego, CA.

Growing evidence indicates that the affinity of monoclonal antibodies (mAbs) for CD16 (Fc{gamma}RIII) plays a central role in the ability of the mAb to mediate antitumor activity. We evaluated how CD16 polymorphisms, and mAb with modified affinity for target antigen and CD16, affect natural killer (NK) cell phenotype when CD20+ malignant B cells were also present. The mAb consisted of rituximab (R), anti-CD20 with enhanced affinity for CD20 (AME-B), and anti-CD20 with enhanced affinity for both CD20 and CD16 (AME-D). Higher concentrations of mAb were needed to induce CD16 modulation, CD54 up-regulation, and antibody-dependent cellular cytotoxicity (ADCC) on NK cells from subjects with the lower affinity CD16 polymorphism. The dose of mAb needed to induce NK activation was lower with AME-D irrespective of CD16 polymorphism. At saturating mAb concentrations, peak NK activation was greater for AME-D. Similar results were found with measurement of CD16 modulation, CD54 up-regulation, and ADCC. These data demonstrate that cells coated with mAb with enhanced affinity for CD16 are more effective at activating NK cells at both low and saturating mAb concentrations irrespective of CD16 polymorphism, and they provide further evidence for the clinical development of such mAbs with the goal of improving clinical response to mAb.


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