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Science 310 (5753): 1510-1512

Copyright © 2005 by the American Association for the Advancement of Science

Divergent Immunoglobulin G Subclass Activity Through Selective Fc Receptor Binding

Falk Nimmerjahn, and Jeffrey V. Ravetch*

Abstract: Subclasses of immunoglobulin G (IgG) display substantial differences in their ability to mediate effector responses, contributing to variable activity of antibodies against microbes and tumors. We demonstrate that the mechanism underlying this long-standing observation of subclass dominance in function is provided by the differential affinities of IgG subclasses for specific activating IgG Fc receptors compared with their affinities for the inhibitory IgG Fc receptor. The significant differences in the ratios of activating-to-inhibitory receptor binding predicted the in vivo activity. We suggest that these highly predictable functions assigned by Fc binding will be an important consideration in the design of therapeutic antibodies and vaccines.

Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.

* To whom correspondence should be addressed. E-mail: ravetch{at}

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Type II (tositumomab) anti-CD20 monoclonal antibody out performs type I (rituximab-like) reagents in B-cell depletion regardless of complement activation.
S. A. Beers, C. H. T. Chan, S. James, R. R. French, K. E. Attfield, C. M. Brennan, A. Ahuja, M. J. Shlomchik, M. S. Cragg, and M. J. Glennie (2008)
Blood 112, 4170-4177
   Abstract »    Full Text »    PDF »
Potent In vitro and In vivo Activity of an Fc-Engineered Anti-CD19 Monoclonal Antibody against Lymphoma and Leukemia.
H. M. Horton, M. J. Bernett, E. Pong, M. Peipp, S. Karki, S. Y. Chu, J. O. Richards, I. Vostiar, P. F. Joyce, R. Repp, et al. (2008)
Cancer Res. 68, 8049-8057
   Abstract »    Full Text »    PDF »
In vivo enzymatic modulation of IgG glycosylation inhibits autoimmune disease in an IgG subclass-dependent manner.
H. Albert, M. Collin, D. Dudziak, J. V. Ravetch, and F. Nimmerjahn (2008)
PNAS 105, 15005-15009
   Abstract »    Full Text »    PDF »
Increased IL-12 inhibits B cells' differentiation to germinal center cells and promotes differentiation to short-lived plasmablasts.
S. J. Kim, M. Caton, C. Wang, M. Khalil, Z.-J. Zhou, J. Hardin, and B. Diamond (2008)
J. Exp. Med. 205, 2437-2448
   Abstract »    Full Text »    PDF »
Impact of a Three Amino Acid Deletion in the CH2 Domain of Murine IgG1 on Fc-Associated Effector Functions.
L. Baudino, F. Nimmerjahn, Y. Shinohara, J.-I. Furukawa, F. Petry, J. S. Verbeek, S.-I. Nishimura, J. V. Ravetch, and S. Izui (2008)
J. Immunol. 181, 4107-4112
   Abstract »    Full Text »    PDF »
Antibody fucosylation differentially impacts cytotoxicity mediated by NK and PMN effector cells.
M. Peipp, J. J. Lammerts van Bueren, T. Schneider-Merck, W. W. K. Bleeker, M. Dechant, T. Beyer, R. Repp, P. H. C. van Berkel, T. Vink, J. G. J. van de Winkel, et al. (2008)
Blood 112, 2390-2399
   Abstract »    Full Text »    PDF »
Optimization of antibody binding to Fc{gamma}RIIa enhances macrophage phagocytosis of tumor cells.
J. O. Richards, S. Karki, G. A. Lazar, H. Chen, W. Dang, and J. R. Desjarlais (2008)
Mol. Cancer Ther. 7, 2517-2527
   Abstract »    Full Text »    PDF »
The Evolution of Multiple Isotypic IgM Heavy Chain Genes in the Shark.
V. Lee, J. L. Huang, M. F. Lui, K. Malecek, Y. Ohta, A. Mooers, and E. Hsu (2008)
J. Immunol. 180, 7461-7470
   Abstract »    Full Text »    PDF »
Recapitulation of IVIG Anti-Inflammatory Activity with a Recombinant IgG Fc.
R. M. Anthony, F. Nimmerjahn, D. J. Ashline, V. N. Reinhold, J. C. Paulson, and J. V. Ravetch (2008)
Science 320, 373-376
   Abstract »    Full Text »    PDF »
Distinct cell-specific control of autoimmunity and infection by Fc{gamma}RIIb.
R. J. Brownlie, K. E. Lawlor, H. A. Niederer, A. J. Cutler, Z. Xiang, M. R. Clatworthy, R. A. Floto, D. R. Greaves, P. A. Lyons, and K. G.C. Smith (2008)
J. Exp. Med. 205, 883-895
   Abstract »    Full Text »    PDF »
Generation of tumour-rejecting anti-carbohydrate monoclonal antibodies using melanoma modified with Fas ligand.
A. K. Simon, T. Newsom-Davis, M. E. F. Frayne, P. F.- T. Ch'en, A. J. McMichael, and G. R. Screaton (2008)
Int. Immunol. 20, 525-534
   Abstract »    Full Text »    PDF »
Destructive Arthritis in the Absence of Both Fc{gamma}RI and Fc{gamma}RIII.
P. Boross, P. L. van Lent, J. Martin-Ramirez, J. van der Kaa, M. H. C. M. Mulder, J. W. C. Claassens, W. B. van den Berg, V. L. Arandhara, and J. S. Verbeek (2008)
J. Immunol. 180, 5083-5091
   Abstract »    Full Text »    PDF »
Tumor Cell Killing Mechanisms of Epidermal Growth Factor Receptor (EGFR) Antibodies Are Not Affected by Lung Cancer-Associated EGFR Kinase Mutations.
M. Peipp, T. Schneider-Merck, M. Dechant, T. Beyer, J. J. Lammerts van Bueren, W. K. Bleeker, P. W. H. I. Parren, J. G. J. van de Winkel, and T. Valerius (2008)
J. Immunol. 180, 4338-4345
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B Lymphocyte Depletion by CD20 Monoclonal Antibody Prevents Diabetes in Nonobese Diabetic Mice despite Isotype-Specific Differences in Fc{gamma}R Effector Functions.
Y. Xiu, C. P. Wong, J.-D. Bouaziz, Y. Hamaguchi, Y. Wang, S. M. Pop, R. M. Tisch, and T. F. Tedder (2008)
J. Immunol. 180, 2863-2875
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Differential Contribution of Three Activating IgG Fc Receptors (Fc{gamma}RI, Fc{gamma}RIII, and Fc{gamma}RIV) to IgG2a- and IgG2b-Induced Autoimmune Hemolytic Anemia in Mice.
L. Baudino, F. Nimmerjahn, S. Azeredo da Silveira, E. Martinez-Soria, T. Saito, M. Carroll, J. V. Ravetch, J. S. Verbeek, and S. Izui (2008)
J. Immunol. 180, 1948-1953
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