دورية أكاديمية
Discovery and Characterization of a Potent Interleukin-6 Binding Peptide with Neutralizing Activity In Vivo.
| العنوان: | Discovery and Characterization of a Potent Interleukin-6 Binding Peptide with Neutralizing Activity In Vivo. |
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| المؤلفون: | Sheila Ranganath, Ashok Bhandari, Nicole Avitahl-Curtis, Jaimee McMahon, Derek Wachtel, Jenny Zhang, Christopher Leitheiser, Sylvie G Bernier, Guang Liu, Tran T Tran, Herodion Celino, Jenny Tobin, Joon Jung, Hong Zhao, Katie E Glen, Chris Graul, Aliesha Griffin, Wayne C Schairer, Carolyn Higgins, Tammi L Reza, Eva Mowe, Sam Rivers, Sonya Scott, Alex Monreal, Courtney Shea, Greg Bourne, Casey Coons, Adaline Smith, Kim Tang, Ramya A Mandyam, Jaime Masferrer, David Liu, Dinesh V Patel, Angelika Fretzen, Craig A Murphy, G Todd Milne, Mark L Smythe, Kenneth E Carlson |
| المصدر: | PLoS ONE, Vol 10, Iss 11, p e0141330 (2015) |
| بيانات النشر: | Public Library of Science (PLoS) |
| سنة النشر: | 2015 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | Medicine, Science |
| الوصف: | Interleukin-6 (IL-6) is an important member of the cytokine superfamily, exerting pleiotropic actions on many physiological processes. Over-production of IL-6 is a hallmark of immune-mediated inflammatory diseases such as Castleman's Disease (CD) and rheumatoid arthritis (RA). Antagonism of the interleukin IL-6/IL-6 receptor (IL-6R)/gp130 signaling complex continues to show promise as a therapeutic target. Monoclonal antibodies (mAbs) directed against components of this complex have been approved as therapeutics for both CD and RA. To potentially provide an additional modality to antagonize IL-6 induced pathophysiology, a peptide-based antagonist approach was undertaken. Using a combination of molecular design, phage-display, and medicinal chemistry, disulfide-rich peptides (DRPs) directed against IL-6 were developed with low nanomolar potency in inhibiting IL-6-induced pSTAT3 in U937 monocytic cells. Targeted PEGylation of IL-6 binding peptides resulted in molecules that retained their potency against IL-6 and had a prolongation of their pharmacokinetic (PK) profiles in rodents and monkeys. One such peptide, PN-2921, contained a 40 kDa polyethylene glycol (PEG) moiety and inhibited IL-6-induced pSTAT3 in U937 cells with sub-nM potency and possessed 23, 36, and 59 h PK half-life values in mice, rats, and cynomolgus monkeys, respectively. Parenteral administration of PN-2921 to mice and cynomolgus monkeys potently inhibited IL-6-induced biomarker responses, with significant reductions in the acute inflammatory phase proteins, serum amyloid A (SAA) and C-reactive protein (CRP). This potent, PEGylated IL-6 binding peptide offers a new approach to antagonize IL-6-induced signaling and associated pathophysiology. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1932-6203 |
| العلاقة: | http://europepmc.org/articles/PMC4640888?pdf=renderTest; https://doaj.org/toc/1932-6203Test; https://doaj.org/article/79b1eaa807e1438c8eaa8708c553dbc5Test |
| DOI: | 10.1371/journal.pone.0141330 |
| الإتاحة: | https://doi.org/10.1371/journal.pone.0141330Test https://doaj.org/article/79b1eaa807e1438c8eaa8708c553dbc5Test |
| رقم الانضمام: | edsbas.9089DF97 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 19326203 |
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| DOI: | 10.1371/journal.pone.0141330 |