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

作者：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

来源：PLos One, 2015, 10(11): e0141330.

DOI：10.1371/journal.pone.0141330

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.

• 出版日期2015-11-10