Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets
Abstract
Inhibitory receptors have been proposed to modulate the in vivo cytotoxic response against tumor targets for both spontaneous and antibody-dependent pathways. Using a variety of syngenic and xenograft models, we demonstrate here that the inhibitory FcgammaRIIB molecule is a potent regulator of antibody-dependent cell-mediated cytotoxicity in vivo, modulating the activity of FcgammaRIII on effector cells. Although many mechanisms have been proposed to account for the anti-tumor activities of therapeutic antibodies, including extended half-life, blockade of signaling pathways, activation of apoptosis and effector-cell-mediated cytotoxicity, we show here that engagement of Fcgamma receptors on effector cells is a dominant component of the in vivo activity of antibodies against tumors. Mouse monoclonal antibodies, as well as the humanized, clinically effective therapeutic agents trastuzumab (Herceptin(R)) and rituximab (Rituxan(R)), engaged both activation (FcgammaRIII) and inhibitory (FcgammaRIIB) antibody receptors on myeloid cells, thus modulating their cytotoxic potential. Mice deficient in FcgammaRIIB showed much more antibody-dependent cell-mediated cytotoxicity; in contrast, mice deficient in activating Fc receptors as well as antibodies engineered to disrupt Fc binding to those receptors were unable to arrest tumor growth in vivo. These results demonstrate that Fc-receptor-dependent mechanisms contribute substantially to the action of cytotoxic antibodies against tumors and indicate that an optimal antibody against tumors would bind preferentially to activation Fc receptors and minimally to the inhibitory partner FcgammaRIIB.
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IgG modulates cellular immune responses through FcγR-binding and direct receptor- or ligand-binding.
“They modulate cellular immune responses through Fcγ receptor (FcγR)-binding as well as through direct receptor- or ligand-binding [9,10].”
From Glycoengineering Chinese hamster ovary cells: a short history (2021) · cites this paper as [10]
In mice lacking FcγRIII and thus deficient in NK cells and macrophages capable of binding the Fc region of trastuzumab, the therapeutic effect of trastuzumab was markedly diminished.
“In mice lacking FcγRIII and, thus, deficient in NK cells and macrophages capable of binding the Fc region of trastuzumab, the therapeutic effect of trastuzumab was markedly diminished (Clynes et al., 2000).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Clynes et al., 2000
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- Authors
- Clynes, R. A., Towers, T. L., Presta, L. G., & Ravetch, J. V.
- Affiliations
- Rockefeller University (US)
- Genentech (US)
- Corresponding author
- Ravetch, Jeffrey V.
- Venue
- Nature Medicine
- Published
- 2000-04
- Volume
- 6
- Issue
- 4
- Pages
- 443-446
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2128402413
- Cited by
- 2,768
- References
- 21
- Citations by year
- 2026: 44 · 2025: 46 · 2024: 66 · 2023: 95 · 2022: 81 · 2021: 66 · 2020: 83 · 2019: 93 · 2018: 93 · 2017: 99 · 2016: 82 · 2015: 141 · 2014: 138 · 2013: 167 · 2012: 158
- FWCI
- 84.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- inhibitory Fc receptor, Fc gamma receptor IIb, Fc gamma receptor III, antibody-dependent cellular cytotoxicity, cancer immunotherapy, therapeutic antibodies, trastuzumab, rituximab, myeloid cells, antibody specificity, antitumor immunity
- MeSH terms
- Trastuzumab, Rituximab, Animals, Antibodies, Monoclonal, Antibody-Dependent Cell Cytotoxicity, Antineoplastic Agents, Female, Humans, Immunization, Passive, Male, Melanoma, Experimental, Mice, Inbred BALB C, Mice, Nude, Antigens, CD, Lymphoma, B-Cell, Receptors, IgG, Erb-b2 Receptor Tyrosine Kinases, Mice, Antibodies, Monoclonal, Murine-Derived, Antibodies, Monoclonal, Humanized
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