2016
DOI: 10.1080/19420862.2016.1226716
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Molecular basis for the mechanism of action of an anti-TACE antibody

Abstract: 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 r… Show more

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Cited by 23 publications
(21 citation statements)
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“…More recently there have been considerable advances in generating function‐blocking Abs of ADAM17 that have greater specificity and a longer half‐life in vivo . For instance, MEDI3622 produced by Medimmune is noteworthy in that its epitope has been mapped to a surface loop unique to the catalytic domain of ADAM17, resulting in exquisite specificity and a potent inhibitory activity . MEDI3622 was originally developed to impair EGFR‐dependent tumor growth, but recently has been shown to block CD16A cleavage from activated human NK cells and markedly enhance their production of IFN‐γ during ADCC .…”
Section: Adam17 As a Regulatory Checkpoint Of Adcc By Nk Cellsmentioning
confidence: 99%
“…More recently there have been considerable advances in generating function‐blocking Abs of ADAM17 that have greater specificity and a longer half‐life in vivo . For instance, MEDI3622 produced by Medimmune is noteworthy in that its epitope has been mapped to a surface loop unique to the catalytic domain of ADAM17, resulting in exquisite specificity and a potent inhibitory activity . MEDI3622 was originally developed to impair EGFR‐dependent tumor growth, but recently has been shown to block CD16A cleavage from activated human NK cells and markedly enhance their production of IFN‐γ during ADCC .…”
Section: Adam17 As a Regulatory Checkpoint Of Adcc By Nk Cellsmentioning
confidence: 99%
“…The combination of MEDI3622 with cetuximab led to complete tumor regression in all mice. MEDI3622 also showed a strong effect in head and neck squamous cell carcinoma xenograft Cal27 (ΔTGI = 112%) and colorectal cancer model H292 (ΔTGI = 110%) …”
Section: Adam Inhibitors: General Considerationsmentioning
confidence: 97%
“…Another ADAM17 inhibitory antibody (MEDI3622) was recently developed and studied in vitro, ex vivo, and in vivo . Binding and molecular modeling studies suggested that MEDI3622 interacted with a unique hairpin loop in ADAM17 which is absent in other ADAMs, ADAMTSs, and MMPs, forming a basis of its isoform specificity (Figure ).…”
Section: Adam Inhibitors: General Considerationsmentioning
confidence: 99%
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“…Another anti‐ADAM17 antibody was developed by MedImmune, LLC. This mAb (MED13622) binds to the Cat domain only and acquires its specificity from binding to the highly variable loop between βIV and βV of the five‐stranded β‐sheet (Rios‐Doria et al ., ; Peng et al, ). It effectively inhibited cancer cell growth in the OE21 oesophageal xenograft model, showing an additive effect with cetuximab (anti‐EGFR).…”
Section: Adamsmentioning
confidence: 99%