Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain

Miles A Miller, Marcia L Moss, Gary K. Powell, Gary Powell, Robert Petrovich, Robert M. Petrovich, Lori Edwards, Lori L. Edwards, Aaron S Meyer, Linda G Griffith, Douglas A Lauffenburger
Scientific reports · 2015 · vol. 5(1) , pp. 15150 · doi:10.1038/srep15150 · PMID:26477568 · PMC4609913 · W1767906215
article OA: gold CC0 ⤵ 1 in-corpus citation
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This study developed a recombinant ADAM12 prodomain inhibitor (PA12) to block HB-EGF shedding and reduce endometriotic cell migration, offering an alternative to decoy antibodies for high-affinity ligands.

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Abstract

Dysregulation of ErbB-family signaling underlies numerous pathologies and has been therapeutically targeted through inhibiting ErbB-receptors themselves or their cognate ligands. For the latter, "decoy" antibodies have been developed to sequester ligands including heparin-binding epidermal growth factor (HB-EGF); however, demonstrating sufficient efficacy has been difficult. Here, we hypothesized that this strategy depends on properties such as ligand-receptor binding affinity, which varies widely across the known ErbB-family ligands. Guided by computational modeling, we found that high-affinity ligands such as HB-EGF are more difficult to target with decoy antibodies compared to low-affinity ligands such as amphiregulin (AREG). To address this issue, we developed an alternative method for inhibiting HB-EGF activity by targeting its cleavage from the cell surface. In a model of the invasive disease endometriosis, we identified A Disintegrin and Metalloproteinase 12 (ADAM12) as a protease implicated in HB-EGF shedding. We designed a specific inhibitor of ADAM12 based on its recombinant prodomain (PA12), which selectively inhibits ADAM12 but not ADAM10 or ADAM17. In endometriotic cells, PA12 significantly reduced HB-EGF shedding and resultant cellular migration. Overall, specific inhibition of ligand shedding represents a possible alternative to decoy antibodies, especially for ligands such as HB-EGF that exhibit high binding affinity and localized signaling.

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Condition tags

endometriosis

MeSH descriptors

ADAM Proteins Autocrine Communication Enzyme Inhibitors Heparin-binding EGF-like Growth Factor Membrane Proteins Recombinant Proteins Signal Transduction ADAM12 Protein ADAM Proteins ADAM Proteins ADAM Proteins Amphiregulin Amphiregulin Antibodies, Monoclonal Antibodies, Monoclonal Cell Line Cell Movement Cell Movement Endometriosis Endometriosis

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