This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van Ojik, H. H. Articles by Weiner, G. J. Search for Related Content PubMed PubMed Citation Articles by van Ojik, H. H. Articles by Weiner, G. J.

CpG-A and B Oligodeoxynucleotides Enhance the Efficacy of Antibody Therapy by Activating Different Effector Cell Populations¹

Department of Medical Oncology, Erasmus MC–Daniel den Hoed Cancer Center, 3000 DR Rotterdam, the Netherlands [H. H. v. O.]; Immunotherapy Laboratory and Department of Immunology, University Medical Center Utrecht, 3584 EA Utrecht, the Netherlands [H. H. v. O., L. B., A. B., M. J. H. J., M. J. v. V., J. G. J. v. d. W.]; Genmab, 3584 CK Utrecht, the Netherlands [M. J. v. V., J. G. J. v. d. W.]; and The Holden Comprehensive Cancer Center and Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242 [C. E. D., G. J. W.]

Immunostimulatory CpG oligodeoxynucleotides (ODNs) can enhance the therapeutic effect of monoclonal antibodies (mAbs) by enhancing antibody-dependent cell-mediated cytotoxicity (ADCC). Distinct classes of CpG ODNs have been found recently to stimulate different effector cell populations. We used murine cancer models to explore the role of various effector cell populations in the antitumor activity seen with mAbs combined with CpG ODNs of the A and B classes. In the 38C13 syngeneic murine lymphoma model, both CpG A and CpG B enhanced the efficacy of murine antilymphoma mAb. Depletion of natural killer (NK) cells alone markedly decreased the efficacy of therapy with mAbs plus CpG A. In contrast, depletion of both NK cells and granulocytes was required to decrease the efficacy of mAb plus CpG B. A human (h) Fc receptor I (FcRI)-expressing transgenic (Tg) mouse model was used to explore the role of FcRI in therapy with mAb and CpG ODN. CpG B induced up-regulation of FcRI in hFcRI Tg mice, whereas CpG A did not. In vitro CpG B also enhanced ADCC of HER-2/neu-expressing tumor cells by the FcRI-directed bispecific antibody MDX-H210 using hFcRI-positive effector cells. In a solid tumor model, tumor growth was inhibited in Tg mice treated with a combination of MDX-H210 and CpG B. These data suggest that CpG A enhance ADCC largely by activating NK cells. In contrast, other effector cell populations, including granulocytes, contribute to the antitumor activity of CpG B and mAbs. FcRI plays an important role in this activity.

This article has been cited by other articles:

				J. P. Leonard, B. K. Link, C. Emmanouilides, S. A. Gregory, D. Weisdorf, J. Andrey, J. Hainsworth, J. A. Sparano, D. E. Tsai, S. Horning, et al. Phase I Trial of Toll-Like Receptor 9 Agonist PF-3512676 with and Following Rituximab in Patients with Recurrent Indolent and Aggressive Non Hodgkin's Lymphoma Clin. Cancer Res., October 15, 2007; 13(20): 6168 - 6174. [Abstract] [Full Text] [PDF]

				V. Damiano, R. Caputo, S. Garofalo, R. Bianco, R. Rosa, G. Merola, T. Gelardi, L. Racioppi, G. Fontanini, S. De Placido, et al. TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts PNAS, July 24, 2007; 104(30): 12468 - 12473. [Abstract] [Full Text] [PDF]

				S. Iida, H. Misaka, M. Inoue, M. Shibata, R. Nakano, N. Yamane-Ohnuki, M. Wakitani, K. Yano, K. Shitara, and M. Satoh Nonfucosylated Therapeutic IgG1 Antibody Can Evade the Inhibitory Effect of Serum Immunoglobulin G on Antibody-Dependent Cellular Cytotoxicity through its High Binding to Fc{gamma}RIIIa. Clin. Cancer Res., May 1, 2006; 12(9): 2879 - 2887. [Abstract] [Full Text] [PDF]

				V. Damiano, R. Caputo, R. Bianco, F. P. D'Armiento, A. Leonardi, S. De Placido, A. R. Bianco, S. Agrawal, F. Ciardiello, and G. Tortora Novel Toll-Like Receptor 9 Agonist Induces Epidermal Growth Factor Receptor (EGFR) Inhibition and Synergistic Antitumor Activity with EGFR Inhibitors Clin. Cancer Res., January 15, 2006; 12(2): 577 - 583. [Abstract] [Full Text] [PDF]

				I. N. Buhtoiarov, H. D. Lum, G. Berke, P. M. Sondel, and A. L. Rakhmilevich Synergistic Activation of Macrophages via CD40 and TLR9 Results in T Cell Independent Antitumor Effects J. Immunol., January 1, 2006; 176(1): 309 - 318. [Abstract] [Full Text] [PDF]

				J. M. Roda, R. Parihar, and W. E. Carson III CpG-Containing Oligodeoxynucleotides Act through TLR9 to Enhance the NK Cell Cytokine Response to Antibody-Coated Tumor Cells J. Immunol., August 1, 2005; 175(3): 1619 - 1627. [Abstract] [Full Text] [PDF]

				J. W. Friedberg, H. Kim, M. McCauley, E. M. Hessel, P. Sims, D. C. Fisher, L. M. Nadler, R. L. Coffman, and A. S. Freedman Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and rituximab in patients with non-Hodgkin lymphoma: increased interferon-{alpha}/{beta}-inducible gene expression, without significant toxicity Blood, January 15, 2005; 105(2): 489 - 495. [Abstract] [Full Text] [PDF]

				J. Christiansen and A. K. Rajasekaran Biological impediments to monoclonal antibody-based cancer immunotherapy Mol. Cancer Ther., November 1, 2004; 3(11): 1493 - 1501. [Abstract] [Full Text] [PDF]

				L. Bevaart, H. H. Van Ojik, A. W. Sun, T. H. Sulahian, J. H. W. Leusen, G. J. Weiner, J. G. J. van de Winkel, and M. J. Van Vugt CpG oligodeoxynucleotides enhance Fc{gamma}RI-mediated cross presentation by dendritic cells Int. Immunol., August 1, 2004; 16(8): 1091 - 1098. [Abstract] [Full Text] [PDF]