An Fcγ Receptor-Dependent Mechanism Drives Antibody-Mediated Target-Receptor Signaling in Cancer Cells

Wilson, Nicholas S.; Yang, Becky; Yang, Annie; Loeser, Stefanie; Marsters, Scot A.; Lawrence, David A.; Li, Yun; Pitti, Robert M.; Tótpál, Klára; Yee, Sharon; Ross, Sarajane; Vernes, Jean-Michel; Lu, Yanmei; Adams, Cam; Offringa, Rienk; Kelley, Bob; Hymowitz, S.G.; Daniel, Dylan; Meng, Gloria; Ashkenazi, Avi

doi:10.1016/j.ccr.2010.11.012

Cited by 235 publications

(245 citation statements)

References 81 publications

(116 reference statements)

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“…We and others have recently found that both agonistic αCD40 and αDR5 antibodies require Fc-FcγR interactions for their in vivo activities and, in contrast to cytotoxic effector antitumor antibodies, these agonistic antibodies require no activating FcγRs, but inhibitory FcγRIIB (14)(15)(16). These studies, together with previous and other recent studies (17,18), have established a general requirement of FcγRIIB for the in vivo activities of agonistic anti-TNFR antibodies (19). In addition, we have also demonstrated that Fcs that preferentially bind to inhibitory FcγRIIB are more potent for agonistic anti-TNFR antibodies, and that the potency of agonistic anti-TNFR antibodies can be enhanced through FcγRIIB-targeted Fc engineering (14,15).…”

mentioning

confidence: 71%

Antitumor activities of agonistic anti-TNFR antibodies require differential FcγRIIB coengagement in vivo

Ravetch

2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Agonistic antibodies targeting key TNF receptor (TNFR) molecules involved in antitumor responses have been demonstrated as potent antitumor therapies in preclinical studies. However, no effective agonistic anti-TNFR therapies have been successfully developed to date. In contrast, cytotoxic antitumor antibodies targeting tumor antigens or antagonistic antibodies blocking key inhibitory checkpoints are widely used in clinical settings. One explanation for this discrepancy has been recently provided by the finding that agonistic anti-TNFR antibodies have a previously unappreciated requirement for inhibitory Fcγ receptor FcγRIIB coengagement. Understanding the differential FcγRIIB coengagement requirement by different antibodies and the in vivo cross-linking function of FcγRIIB, as defined by this study, not only has implications for the development of potent agonistic anti-TNFR therapies but also for the understanding of TNFR activation mechanisms.

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mentioning

confidence: 71%

Antitumor activities of agonistic anti-TNFR antibodies require differential FcγRIIB coengagement in vivo

Ravetch

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Furthermore, TRAIL-induced apoptosis can proceed independent of protein neosynthesis, explaining why a systems analysis of baseline protein expression is sufficient to predict TRAIL responsiveness. As TRAIL ligands are currently investigated in clinical trials and as improved second generation ligands are currently in preclinical development, 30,31 our systems approach may provide possibilities to identify TRAIL-responsive melanoma by molecular profiling, and by extension may assist in patient stratification as part of future clinical trial designs. We also predicted DTIC-induced cell death, albeit with slightly lower accuracy.…”

Section: Discussionmentioning

confidence: 99%

Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells

et al. 2013

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Many cancer entities and their associated cell line models are highly heterogeneous in their responsiveness to apoptosis inducers and, despite a detailed understanding of the underlying signaling networks, cell death susceptibility currently cannot be predicted reliably from protein expression profiles. Here, we demonstrate that an integration of quantitative apoptosis protein expression data with pathway knowledge can predict the cell death responsiveness of melanoma cell lines. By a total of 612 measurements, we determined the absolute expression (nM) of 17 core apoptosis regulators in a panel of 11 melanoma cell lines, and enriched these data with systems-level information on apoptosis pathway topology. By applying multivariate statistical analysis and multi-dimensional pattern recognition algorithms, the responsiveness of individual cell lines to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or dacarbazine (DTIC) could be predicted with very high accuracy (91 and 82% correct predictions), and the most effective treatment option for individual cell lines could be pre-determined in silico. In contrast, cell death responsiveness was poorly predicted when not taking knowledge on protein-protein interactions into account (55 and 36% correct predictions). We also generated mathematical predictions on whether anti-apoptotic Bcl-2 family members or x-linked inhibitor of apoptosis protein (XIAP) can be targeted to enhance TRAIL responsiveness in individual cell lines. Subsequent experiments, making use of pharmacological Bcl-2/Bcl-xL inhibition or siRNA-based XIAP depletion, confirmed the accuracy of these predictions. We therefore demonstrate that cell death responsiveness to TRAIL or DTIC can be predicted reliably in a large number of melanoma cell lines when investigating expression patterns of apoptosis regulators in the context of their network-level interplay. The capacity to predict responsiveness at the cellular level may contribute to personalizing anti-cancer treatments in the future.

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“…22 Antibody crosslinking by immune cells expressing Fcg-receptors such as leukocytes can be therapeutically beneficial by triggering pro-apoptotic stimuli in cancer cells. 21 This effect can be mimicked in vitro by using an anti-Fc antibody, such as a polyclonal goat anti-human IgG, AbXL.…”

Section: Ign523 Elicits Caspase-dependent Apoptosis Increases Lysosomentioning

confidence: 99%

Antitumor activity of an anti‐CD98 antibody

et al. 2015

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CD98 is expressed on several tissue types and specifically upregulated on fast-cycling cells undergoing clonal expansion. Various solid (e.g., nonsmall cell lung carcinoma) as well as hematological malignancies (e.g., acute myeloid leukemia) overexpress CD98. We have identified a CD98-specific mouse monoclonal antibody that exhibits potent preclinical antitumor activity against established lymphoma tumor xenografts. Additionally, the humanized antibody designated IGN523 demonstrated robust tumor growth inhibition in leukemic cell-line derived xenograft models and was as efficacious as standard of care carboplatin in patient-derived nonsmall lung cancer xenografts. In vitro studies revealed that IGN523 elicited strong ADCC activity, induced lysosomal membrane permeabilization and inhibited essential amino acid transport function, ultimately resulting in caspase-3 and -7-mediated apoptosis of tumor cells. IGN523 is currently being evaluated in a Phase I clinical trial for acute myeloid leukemia (NCT02040506). Furthermore, preclinical data support the therapeutic potential of IGN523 in solid tumors.CD98 is a heterodimeric protein that comprises a heavy and light chain. The CD98 heavy chain is a type II transmembrane glycoprotein that forms a heterodimer via covalent linkage to one of 6 amino acid transporters. 1,2 CD98 is overexpressed on the cell surface of almost all tumor cells, regardless of tissue origin and increased expression of a CD98-light chain, L-type amino acid transporter 1 (LAT-1) occurs in many types of human cancers, including breast, colon, oral, ovarian, esophageal, glioma and leukemia. 3,4 Increased uptake of amino acids supports the high growth rate of cancer cells by providing the building blocks for protein synthesis. [4][5][6] Moreover, the higher expression of CD98 heavy chain and LAT-1 in metastatic vs. primary tumors suggests that over-expression of CD98/LAT-1 may facilitate progression and metastasis of human cancers.CD98 also regulates integrin signaling by association with integrin b-subunits, thereby controlling cell proliferation, survival, migration, epithelial adhesion and polarity. 3,7 The function of CD98 in regulating both amino acid transport and integrin signaling can contribute to the rapid proliferation and clonal expansion of lymphocytes and tumor cells. 3 The expression pattern and pleiotropic function of CD98 heavy and light chains suggest these proteins are promising targets for treatment of a variety of human cancers. Although small molecule inhibitors of LAT-1 activity have demonstrated preclinical antitumor activity in a number of cancer cell types, including NSCLC, colon cancer, oral cancer and breast cancer, development of antibodies against CD98 heavy chain has received less focus. 5,[8][9][10] Murine monoclonal antibodies to CD98 inhibit lymphocyte proliferation and the growth of bladder cancer, lymphoma, glioma, prostate and colon cancer cells in preclinical models. [11][12][13] To identify therapeutic anti-CD98 antibodies with significant antitumor activity, we ...

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An Fcγ Receptor-Dependent Mechanism Drives Antibody-Mediated Target-Receptor Signaling in Cancer Cells

Cited by 235 publications

References 81 publications

Antitumor activities of agonistic anti-TNFR antibodies require differential FcγRIIB coengagement in vivo

Antitumor activities of agonistic anti-TNFR antibodies require differential FcγRIIB coengagement in vivo

Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells

Antitumor activity of an anti‐CD98 antibody

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