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Science 333 (6045): 1030-1034

Copyright © 2011 by the American Association for the Advancement of Science

Inhibitory Fc{gamma} Receptor Engagement Drives Adjuvant and Anti-Tumor Activities of Agonistic CD40 Antibodies

Fubin Li, and Jeffrey V. Ravetch*

Abstract: CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, is expressed on antigen-presenting cells (APCs) and is essential for immune activation. Although agonistic CD40 antibodies have been developed for immunotherapy, their clinical efficacy has been limited. We have found that coengagement of the Fc domain of agonistic CD40 monoclonal antibodies (mAbs) with the inhibitory Fc{gamma} receptor Fc{gamma}RIIB is required for immune activation. Direct comparison of mAbs to CD40 enhanced for activating Fc{gamma}R binding, hence capable of cytotoxicity, or for inhibitory Fc{gamma}RIIB binding, revealed that enhancing Fc{gamma}RIIB binding conferred immunostimulatory activity and considerably greater anti-tumor responses. This unexpected requirement for Fc{gamma}RIIB in enhancing CD40-mediated immune activation has direct implications for the design of agonistic antibodies to TNFR as therapeutics.

Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA.
* To whom correspondence should be addressed. E-mail: ravetch{at}

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Ex Vivo Assays of Dendritic Cell Activation and Cytokine Profiles as Predictors of In Vivo Effects in an Anti-Human CD40 Monoclonal Antibody ChiLob 7/4 Phase I Trial.
F. Chowdhury, P. W. Johnson, M. J. Glennie, and A. P. Williams (2014)
Cancer Immunology 2, 229-240
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Asymmetrical Fc Engineering Greatly Enhances Antibody-dependent Cellular Cytotoxicity (ADCC) Effector Function and Stability of the Modified Antibodies.
Z. Liu, K. Gunasekaran, W. Wang, V. Razinkov, L. Sekirov, E. Leng, H. Sweet, I. Foltz, M. Howard, A.-M. Rousseau, et al. (2014)
J. Biol. Chem. 289, 3571-3590
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Vaccination with a Fusion Protein That Introduces HIV-1 Gag Antigen into a Multitrimer CD40L Construct Results in Enhanced CD8+ T Cell Responses and Protection from Viral Challenge by Vaccinia-Gag.
S. Gupta, J. M. Termini, F. N. Raffa, C.-A. Williams, R. S. Kornbluth, and G. W. Stone (2014)
J. Virol. 88, 1492-1501
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Role of Crosslinking for Agonistic CD40 Monoclonal Antibodies as Immune Therapy of Cancer.
L. P. Richman and R. H. Vonderheide (2014)
Cancer Immunology 2, 19-26
   Abstract »    Full Text »    PDF »
Antitumor activities of agonistic anti-TNFR antibodies require differential Fc{gamma}RIIB coengagement in vivo.
F. Li and J. V. Ravetch (2013)
PNAS 110, 19501-19506
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Agonist Anti-Human CD27 Monoclonal Antibody Induces T Cell Activation and Tumor Immunity in Human CD27-Transgenic Mice.
L.-Z. He, N. Prostak, L. J. Thomas, L. Vitale, J. Weidlick, A. Crocker, C. D. Pilsmaker, S. M. Round, A. Tutt, M. J. Glennie, et al. (2013)
J. Immunol. 191, 4174-4183
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Immunotherapy Targeting Inhibitory Fc{gamma} Receptor IIB (CD32b) in the Mouse Is Limited by Monoclonal Antibody Consumption and Receptor Internalization.
E. L. Williams, A. L. Tutt, S. A. Beers, R. R. French, C. H. T. Chan, K. L. Cox, A. Roghanian, C. A. Penfold, C. L. Butts, P. Boross, et al. (2013)
J. Immunol. 191, 4130-4140
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Effects of CD40 ligation combined with chemotherapy drugs on human breast cancer cell lines.
Z.-Q. Wang, J. Wang, W.-H. Ling, X.-G. Zhang, and Q. Shi (2013)
Journal of International Medical Research 41, 1495-1504
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Engineered antibody Fc variant with selectively enhanced Fc{gamma}RIIb binding over both Fc{gamma}RIIaR131 and Fc{gamma}RIIaH131.
F. Mimoto, H. Katada, S. Kadono, T. Igawa, T. Kuramochi, M. Muraoka, Y. Wada, K. Haraya, T. Miyazaki, and K. Hattori (2013)
Protein Eng. Des. Sel. 26, 589-598
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Fc{gamma} receptors enable anticancer action of proapoptotic and immune-modulatory antibodies.
J. M. Kim and A. Ashkenazi (2013)
J. Exp. Med. 210, 1647-1651
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Making Macrophages Eat Cancer.
M. H. Kershaw and M. J. Smyth (2013)
Science 341, 41-42
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Multivalent Scaffold Proteins as Superagonists of TRAIL Receptor 2-Induced Apoptosis.
J. S. Swers, L. Grinberg, L. Wang, H. Feng, K. Lekstrom, R. Carrasco, Z. Xiao, I. Inigo, C. C. Leow, H. Wu, et al. (2013)
Mol. Cancer Ther. 12, 1235-1244
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T Cell Costimulation with Anti-CD137 Monoclonal Antibodies Is Mediated by K63-Polyubiquitin-Dependent Signals from Endosomes.
I. Martinez-Forero, A. Azpilikueta, E. Bolanos-Mateo, E. Nistal-Villan, A. Palazon, A. Teijeira, G. Perez-Chacon, A. Morales-Kastresana, O. Murillo, M. Jure-Kunkel, et al. (2013)
J. Immunol. 190, 6694-6706
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Agonistic Anti-CD40 Induces Thyrocyte Proliferation and Promotes Thyroid Autoimmunity by Increasing CD40 Expression on Thyroid Epithelial Cells.
T. Kayes, Y. Fang, S. Yu, E. Downey, S. Wang, and H. Braley-Mullen (2013)
J. Immunol. 190, 3928-3938
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Agonistic CD40 Antibodies and Cancer Therapy.
R. H. Vonderheide and M. J. Glennie (2013)
Clin. Cancer Res. 19, 1035-1043
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Fc-fusion proteins: new developments and future perspectives.
D. M. Czajkowsky, J. Hu, Z. Shao, and R. J. Pleass (2012)
EMBO Mol Med. 4, 1015-1028
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Apoptotic and antitumor activity of death receptor antibodies require inhibitory Fc{gamma} receptor engagement.
F. Li and J. V. Ravetch (2012)
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Properties of mouse and human IgG receptors and their contribution to disease models.
P. Bruhns (2012)
Blood 119, 5640-5649
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Mouse model recapitulating human Fc{gamma} receptor structural and functional diversity.
P. Smith, D. J. DiLillo, S. Bournazos, F. Li, and J. V. Ravetch (2012)
PNAS 109, 6181-6186
   Abstract »    Full Text »    PDF »
The Adjuvant Effects of Antibodies.
M. J. Smyth and M. H. Kershaw (2011)
Science 333, 944-945
   Abstract »    Full Text »    PDF »

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