To date, two anti-ADAM17 inhibitory mAbs, D1(A12) and MED13622, have shown moderate to high efficacy in vitro and in vivo tumor models of triple-negative breast, head and neck squamous cell epithelial, as well as ovarian and esophageal, cancers , , . vs Lupulone PBS). Treatment with D8P1C1 did not affect mouse weight (B) although it binds both human and mouse ADAM17. Panel (C) shows representative tumors excised from the treated and untreated animals. Discussion ADAM17 is a member of the ADAM family of metalloproteinases. It cleaves over 80 substrates that are involved in tumor progression, inflammation and neurological diseases. In addition to erbB ligands as discussed above, substrates include Jagged1 , Glypican  and the C-MET receptor  that are primarily responsible for metastasis, cell proliferation and maintenance of stem cell populations in a wide variety of solid and hematological cancers . ADAM17 also cleaves substrates, such as Neogenin , Syndecan-4  and Glycoprotein VI, which augment inflammatory pathways . It has been documented that ADAM17 sheds the Fc receptor CD16 that is present on peripheral blood natural killer (NK) cells and over-activation of ADAM17 dampens the effector functions Nt5e of NK cells by downregulating the cell surface expression of CD16. ADAM17 antagonists play a major role in restoring the effector functions of NK cells . Furthermore, ADAM17 is upregulated Lupulone or mutated in many cancers (Fig. S2). Consequently, ADAM17 is considered to be an attractive target for therapeutic intervention. Several small molecule inhibitors targeting the catalytic domain of ADAM17 have been previously developed, such as Apratastat (Wyeth pharmaceuticals), DPC 333 (Bristol-Myers SquibbCompany) and INCB7839 (Incyte corporation), but they failed in clinical trials due to their toxicity and lack of specificity . This is mainly because the inhibitors also target a close homolog of ADAM17, ADAM10, and some essential matrix metalloproteinases, such as MMP2, MM12, MMP15 . Further chemical modifications of these compounds are in progress. A quinoline-derivative of the hydoxamate-based inhibitors DPC-33 and Apratastat was shown to inhibit proliferation of human keratinocytes with an IC50 of 3?nM and has been selected as a clinical candidate for psoriasis. Non-hydroxamate and non-zinc binding inhibitors of ADAM17 have also been investigated in cell-based assays but none has been tested in clinical trials . Thus, monoclonal antibodies targeting ADAM17 are suggested to provide a better arsenal to deter cancer progression. To date, two anti-ADAM17 inhibitory Lupulone mAbs, D1(A12) and MED13622, have shown moderate to high efficacy in vitro and in vivo tumor models of triple-negative breast, head and neck squamous cell epithelial, as well as ovarian and esophageal, cancers , , . Binding and modeling studies indicate that D1(A12) binds to both the catalytic and noncatalytic ADAM17 domains while MED13622 binds a unique hairpin loop in the ADAM17 metalloprotease domain. This loop is absent in other ADAMs, ADAMTSs and MMPs explaining the basis for the mAb’s specificity . Here we Lupulone describe the generation and anti-tumor potential of a new anti-ADAM17 mAb, D8P1C1. D8P1C1 inhibits proliferation of a host of cancer cell lines, including TNBC and HER2-overexpressing breast, ovarian, glioma, colon and non-small cell lung cancer lines. Though the inhibitory effect is modest in ovarian, glioma and colon cancer cells, it is significant in the case of the two breast cancer cell lines MDA-MB-231 (TNBC) and SKBR-3 (HER2 overexpressing), as well as the non-small cell lung cancer cell line HCC-827 that has an acquired mutation in the tyrosine kinase domain (E746-E750) . Importantly, in an in vivo xenograft model.