A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

Rios-Doria, Jonathan; Sabol, Darrin; Chesebrough, Jon; Stewart, D. Jeremy; Xu, Linda; Tammali, Ravinder; Cheng, Li; Du, Qun; Schifferli, Kevin; Rothstein, Ray; Leow, Ching Ching; Heidbrink-Thompson, Jenny; Jin, Xiaofang; Gao, Changshou; Friedman, Jay; Wilkinson, Brandy; Damschroder, Melissa; Pierce, Andrew J.; Hollingsworth, Robert E.; Tice, David A.; Michelotti, Emil F.

doi:10.1158/1535-7163.mct-14-1040

Cited by 46 publications

(63 citation statements)

References 41 publications

(43 reference statements)

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“…Insofar, ADAM17 is a promising target as inhibition of its proteolytic activity not only affects a single receptor tyrosine kinase, for example, the EGFR, and its downstream signal transduction cascades, but deregulates multiple auto-and paracrine-controlled processes. Only recently novel ADAM17-directed inhibitory antibodies have been developed and demonstrated broad antitumor potency both in EGFR ligand-dependent and -independent tumor cells (42,43). While EGFR-directed agents, also in combination with radiotherapy, are a promising treatment strategy, many tumors rapidly acquire resistance during the course of treatment.…”

Section: Discussionmentioning

confidence: 99%

Secretome Signature Identifies ADAM17 as Novel Target for Radiosensitization of Non–Small Cell Lung Cancer

Sharma

Bender

Zimmermann

et al. 2016

Clinical Cancer Research

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Purpose: Ionizing radiation (IR) induces intracellular signaling processes as part of a treatment-induced stress response. Here we investigate IR-induced ADAM17 activation and the role of ADAM17-shed factors for radiation resistance in non-small cell lung cancer.Experimental Design: Large-scale secretome profiling was performed using antibody arrays. Secretion kinetics of ADAM17 substrates was determined using ELISA across multiple in vitro and in vivo models of non-small cell lung cancer. Clonogenic survival and tumor xenograft assays were performed to determine radiosensitization by ADAM17 inhibition.Results: On the basis of a large-scale secretome screening, we investigated secretion of auto-or paracrine factors in non-small cell lung cancer in response to irradiation and discovered the ADAM17 network as a crucial mediator of resistance to IR. Irradiation induced a dose-dependent increase of furin-mediated cleavage of the ADAM17 proform to active ADAM17, which resulted in enhanced ADAM17 activity in vitro and in vivo. Genetic or pharmacologic targeting of ADAM17 suppressed IR-induced shedding of secreted factors, downregulated ErbB signaling in otherwise cetuximab-resistant target cells, and enhanced IRinduced cytotoxicity. The combined treatment modality of IR with the ADAM17 inhibitor TMI-005 resulted in a supra-additive antitumor response in vivo demonstrating the potential of ADAM17 targeting in combination with radiotherapy.Conclusions: Radiotherapy activates ADAM17 in non-small cell lung cancer, which results in shedding of multiple survival factors, growth factor pathway activation, and IR-induced treatment resistance. We provide a sound rationale for repositioning ADAM17 inhibitors as short-term adjuvants to improve the radiotherapy outcome of non-small cell lung cancer. Clin Cancer Res; 22(17); 4428-39. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Secretome Signature Identifies ADAM17 as Novel Target for Radiosensitization of Non–Small Cell Lung Cancer

Sharma

Bender

Zimmermann

et al. 2016

Clinical Cancer Research

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“…47,48 A second monoclonal antibody against ADAM17 with anticancer activity was recently described. 49 This antibody, dubbed MED13622, was found to inhibit cancer cell growth in several different preclinical systems. Response to MED13622 was found to correlate with sensitivity to the anti-EGFR antibody, cetuximab across a large panel of cell lines of diverse origins.…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

The ADAMs family of proteases as targets for the treatment of cancer

Mullooly

McGowan

Crown

et al. 2016

Cancer Biology & Therapy

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The ADAMs (a disintegrin and metalloproteases) are transmembrane multidomain proteins implicated in multiple biological processes including proteolysis, cell adhesion, cell fusion, cell proliferation and cell migration. Of these varied activities, the best studied is their role in proteolysis. However, of the 22 ADAMs believed to be functional in humans, only approximately a half possess matrix metalloproteinase (MMP)-like protease activity. In contrast to MMPs which are mostly implicated in the degradation of extracellular matrix proteins, the main ADAM substrates are the ectodomains of type I and type II transmembrane proteins. These include growth factor/cytokine precursors, growth factor/cytokine receptors and adhesion proteins. Recently, several different ADAMs, especially ADAM17, have been shown to play a role in the development and progression of multiple cancer types. Consistent with this role in cancer, targeting ADAM17 with either low molecular weight inhibitors or monoclonal antibodies was shown to have anticancer activity in multiple preclinical systems. Although early phase clinical trials have shown no serious side effects with a dual ADAM10/17 low molecular weight inhibitor, the consequences of long-term treatment with these agents is unknown. Furthermore, efficacy in clinical trials remains to be shown.

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“…1A). ADAM10 was chosen because it is the closest homolog to TACE, but not recognized by MEDI3622 14 . The chimeric variants were constructed to encode full-length proteins with transmembrane and cytoplasmic domains, and were expressed on the surface of human embryonic kidney (HEK) 293F cells.…”

Section: Resultsmentioning

confidence: 99%

“…A specific TACE inhibitory antibody, MEDI3622 (IgG1, κ), that efficiently inhibited shedding of TACE substrates, such as EGFR-ligands and TNF-α, was recently reported 14 . MEDI3622 was shown to induce tumor regression or stasis in multiple EGFR-dependent tumor models 14 .…”

Section: Introductionmentioning

confidence: 99%

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Molecular basis for the mechanism of action of an anti-TACE antibody

Li¹,

Cook²,

Xu³

et al. 2016

mAbs

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Inhibitors of tumor necrosis factor-α converting enzyme (TACE) have potential as therapeutics for various diseases. Many small molecule inhibitors, however, exhibit poor specificity profiles because they target the highly conserved catalytic cleft of TACE. We report for the first time the molecular interaction of a highly specific anti-TACE antagonistic antibody (MEDI3622). We characterized the binding of MEDI3622 using mutagenesis, as well as structural modeling and docking approaches. We show that MEDI3622 recognizes a unique surface loop of sIVa-sIVb β-hairpin on TACE M-domain, but does not interact with the conserved catalytic cleft or its nearby regions. The exquisite specificity of MEDI3622 is mediated by this distinct structural feature on the TACE M-domain. These findings may aid the design of antibody therapies against TACE.

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A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

Cited by 46 publications

References 41 publications

Secretome Signature Identifies ADAM17 as Novel Target for Radiosensitization of Non–Small Cell Lung Cancer

Secretome Signature Identifies ADAM17 as Novel Target for Radiosensitization of Non–Small Cell Lung Cancer

The ADAMs family of proteases as targets for the treatment of cancer

Molecular basis for the mechanism of action of an anti-TACE antibody

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