PLoS ONE (Jan 2015)

Discovery and Characterization of a Potent Interleukin-6 Binding Peptide with Neutralizing Activity In Vivo.

  • 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

DOI
https://doi.org/10.1371/journal.pone.0141330
Journal volume & issue
Vol. 10, no. 11
p. e0141330

Abstract

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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.