Discovery and characterization of a potent interleukin-6 binding peptide with neutralizing activity in vivo

Ranganath, Sheila, Bhandari, Ashok, Avitahl-Curtis, Nicole, McMahon, Jaimee, Wachtel, Derek, Zhang, Jenny, Leitheiser, Christopher, Bernier, Sylvie G., Liu, Guang, Tran, Tran T., Celino, Herodion, Tobin, Jenny, Jung, Joon, Zhao, Hong, Glen, Katie E., Graul, Chris, Griffin, Aliesha, Schairer, Wayne C., Higgins, Carolyn, Reza, Tammi L., Mowe, Eva, Rivers, Sam, Scott, Sonya, Monreal, Alex, Shea, Courtney, Bourne, Greg, Coons, Casey, Smith, Adaline, Tang, Kim, Mandyam, Ramya A., Masferrer, Jaime, Liu, David, Patel, Dinesh V., Fretzen, Angelika, Murphy, Craig A., Milne, G. Todd, Smythe, Mark L. and Carlson, Kenneth E. (2015) Discovery and characterization of a potent interleukin-6 binding peptide with neutralizing activity in vivo. PLoS One, 10 11: 1-19. doi:10.1371/journal.pone.0141330


Author Ranganath, Sheila
Bhandari, Ashok
Avitahl-Curtis, Nicole
McMahon, Jaimee
Wachtel, Derek
Zhang, Jenny
Leitheiser, Christopher
Bernier, Sylvie G.
Liu, Guang
Tran, Tran T.
Celino, Herodion
Tobin, Jenny
Jung, Joon
Zhao, Hong
Glen, Katie E.
Graul, Chris
Griffin, Aliesha
Schairer, Wayne C.
Higgins, Carolyn
Reza, Tammi L.
Mowe, Eva
Rivers, Sam
Scott, Sonya
Monreal, Alex
Shea, Courtney
Bourne, Greg
Coons, Casey
Smith, Adaline
Tang, Kim
Mandyam, Ramya A.
Masferrer, Jaime
Liu, David
Patel, Dinesh V.
Fretzen, Angelika
Murphy, Craig A.
Milne, G. Todd
Smythe, Mark L.
Carlson, Kenneth E.
Title Discovery and characterization of a potent interleukin-6 binding peptide with neutralizing activity in vivo
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2015-11
Year available 2015
Sub-type Article (original research)
DOI 10.1371/journal.pone.0141330
Open Access Status DOI
Volume 10
Issue 11
Start page 1
End page 19
Total pages 19
Place of publication San Francisco, CA United States
Publisher Public Library of Science
Collection year 2016
Language eng
Abstract 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.
Keyword Classification
Protein
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
 
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