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

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

  • PLoS One. 2015 Nov 10;10(11):e0141330. doi: 10.1371/journal.pone.0141330.
Sheila Ranganath 1,  Ashok Bhandari 2,  Nicole Avitahl-Curtis 3,  Jaimee McMahon 4,  Derek Wachtel 5,  Jenny Zhang 4,  Christopher Leitheiser 6,  Sylvie G Bernier 1,  Guang Liu 1,  Tran T Tran 7,  Herodion Celino 2,  Jenny Tobin 3,  Joon Jung 8,  Hong Zhao 6,  Katie E Glen 4,  Chris Graul 3,  Aliesha Griffin 4,  Wayne C Schairer 6,  Carolyn Higgins 5,  Tammi L Reza 9,  Eva Mowe 4,  Sam Rivers 3,  Sonya Scott 4,  Alex Monreal 1,  Courtney Shea 3,  Greg Bourne 4 7,  Casey Coons 6,  Adaline Smith 9,  Kim Tang 3,  Ramya A Mandyam 4,  Jaime Masferrer 3,  David Liu 10,  Dinesh V Patel 2,  Angelika Fretzen 6,  Craig A Murphy 4 7,  G Todd Milne 1,  Mark L Smythe 4 7,  Kenneth E Carlson 1
Affiliations

Affiliations

  • 1 Discovery Biology, Ironwood Pharmaceuticals, Cambridge, MA, United States of America.
  • 2 Chemistry, Protagonist Therapeutics, Milpitas, CA, United States of America.
  • 3 Discovery Pharmacology, Ironwood Pharmaceuticals, Cambridge, MA, United States of America.
  • 4 Institute for Molecular Biosciences, The University of Queensland, Brisbane, Australia.
  • 5 DMPK, Ironwood Pharmaceuticals, Cambridge, MA, United States of America.
  • 6 Pharmaceutical Development, Ironwood Pharmaceuticals, Cambridge, MA, United States of America.
  • 7 Protagonist Pty Ltd, Therapeutics Pty Ltd, Brisbane, Australia.
  • 8 Chemistry, Ironwood Pharmaceuticals, Cambridge, MA, United States of America.
  • 9 Discovery Toxicology, Ironwood Pharmaceuticals, Cambridge, MA, United States of America.
  • 10 Biology, Protagonist Therapeutics, Milpitas, CA, United States of America.
PMID: 26555695 DOI: 10.1371/journal.pone.0141330
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.

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