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Featured researches published by Sarah Sague.


mAbs | 2010

Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor α.

David Shealy; Ann Cai; Kim Staquet; Audrey Baker; Eilyn R. Lacy; Laura Johns; Omid Vafa; George R. Gunn; Susan Tam; Sarah Sague; Dana Wang; Mike Brigham-Burke; Paul Dalmonte; Eva Emmell; Bill Pikounis; Peter J. Bugelski; Honghui Zhou; Bernard Scallon; Jill Giles-Komar

We prepared and characterized golimumab (CNTO148), a human IgG1 tumor necrosis factor alpha (TNFα) antagonist monoclonal antibody chosen for clinical development based on its molecular properties. Golimumab was compared with infliximab, adalimumab and etanercept for affinity and in vitro TNFα neutralization. The affinity of golimumab for soluble human TNFα, as determined by surface plasmon resonance, was similar to that of etanercept (18 pM versus 11 pM), greater than that of infliximab (44 pM) and significantly greater than that of adalimumab (127 pM, p=0.018). The concentration of golimumab necessary to neutralize TNFα-induced E-selectin expression on human endothelial cells by 50% was significantly less than those for infliximab (3.2 fold; p=0.017) and adalimumab (3.3-fold; p=0.008) and comparable to that for etanercept. The conformational stability of golimumab was greater than that of infliximab (primary melting temperature [Tm] 74.8 °C vs. 69.5 °C) as assessed by differential scanning calorimetry. In addition, golimumab showed minimal aggregation over the intended shelf life when formulated as a high concentration liquid product (100 mg/mL) for subcutaneous administration. In vivo, golimumab at doses of 1 and 10 mg/kg significantly delayed disease progression in a mouse model of human TNFα-induced arthritis when compared with untreated mice, while infliximab was effective only at 10 mg/kg. Golimumab also significantly reduced histological scores for arthritis severity and cartilage damage, as well as serum levels of pro-inflammatory cytokines and chemokines associated with arthritis. Thus, we have demonstrated that golimumab is a highly stable human monoclonal antibody with high affinity and capacity to neutralize human TNFα in vitro and in vivo.


Journal of Pharmacology and Experimental Therapeutics | 2010

GLP-2 Receptor Agonism Ameliorates Inflammation and Gastrointestinal Stasis in Murine Postoperative Ileus

Nancy Peffer; Allison Pirone; Ashlyn E. Bassiri; Sarah Sague; Jeffrey M. Palmer; Dana L. Johnson; Tom Nesspor; Connie M. Kliwinski; Pamela J. Hornby

Glucagon-like peptide 2 (GLP-2) is a pleiotropic intestinotrophic hormone that we hypothesized could lessen gastrointestinal inflammation associated with postoperative ileus (POI). To test this idea, the prophylactic timing and dose of a long-acting variant of human GLP-2 linked to the Fc portion of murine immunoglobulin G (IgG) (GLP-2/IgG) was optimized in a murine model of POI. Surgically treated mice received a single dose of GLP-2/IgG, IgG isotype control, or phosphate-buffered saline 1 to 48 h before small bowel surgical manipulation. The distribution of orally fed fluorescein isothiocyanate-dextran and histological analyses of myeloperoxidase-positive immune cells were determined 24 and 48 h postoperatively. TaqMan quantitative polymerase chain reaction was used to determine early changes in mRNA expression in the muscularis or mucosa. In normal mice, prolonged exposure to GLP-2 increased upper gastrointestinal (GI) transit and mucosal weight. When administered 1 or 3 h before surgery, GLP-2/IgG reduced the leukocyte infiltrate 24 and 48 h postoperatively and improved GI transit 48 h postoperatively. Surgical manipulation rapidly increased gene expression of proinflammatory cytokines and enzymes for kinetically active mediators in the mucosa and muscularis. GLP-2/IgG2a affected the expression of genes associated with mucosal inflammation and barrier function. We conclude that prophylactic treatment with a long-acting GLP-2 agonist ameliorates inflammation and improves intestinal dysmotility associated with surgical manipulation of the bowel. The action of GLP-2 is consistent with a lessening of inflammation, leading to a more rapid recovery.


Nephron Experimental Nephrology | 2011

Proinflammatory/Profibrotic Effects of Interleukin-17A on Human Proximal Tubule Epithelium

Paul L. Dudas; Sarah Sague; M. Merle Elloso; Francis X. Farrell

Background/Aims: Interleukin-17A (IL-17A) is a T cell-derived inflammatory cytokine that is upregulated during renal allograft rejection. The present study sought to further describe the IL-17A-mediated proinflammatory/profibrotic activity of proximal tubule epithelium that may contribute to allograft rejection. Methods: Immortalized (HK-2) and primary (HRPTEpiC) human proximal tubule epithelial cells were utilized for this study. Profibrotic gene alterations were examined by real-time quantitative PCR. Inflammatory mediator secretion was examined by multiplex bead-based detection of secreted proteins. Immunofluorescence microscopy and immunoblotting were utilized to examine alterations in junctional protein expression and cell morphology. Results: In HK-2 cells IL-17A significantly downregulated the expression of the proepithelial gene CDH1 (E-cadherin) while the proinflammatory/profibrotic genes CTGF, CD44 and TGFBR1 were significantly increased. IL-17A also increased the secretion of fractalkine, G-CSF, GM-CSF, VEGF, IL-6 and IL-8. In HRPTEpiC 100 ng/ml IL-17A upregulated the proinflammatory/profibrotic genes ACTA2, CCL2, CHMP1A, CTGF, FN1, IL6, FSP1, SMAD1, SMAD5, TGFB1 and TGFBR2 while treatment with a reduced concentration of IL-17A (0.1 ng/ml) decreased SMAD5, TGFB1 and PDGFRB expression. Changes in ZO-1 and E-cadherin protein expression and cell morphology were examined following IL-17A treatment as indicators of epithelial-to-mesenchymal transition. IL-17A decreased ZO-1 expression in HK-2 and HRPTEpiC; however, E-cadherin was only reduced in HK-2 cells. Neither HK-2 nor HRPTEpiC assumed an elongated, fibroblast-like morphology following IL-17A treatment. Conclusions: IL-17A directly mediates proximal tubule epithelial cell proinflammatory/profibrotic activity as demonstrated by the alteration in genes associated with extracellular matrix remodeling and cell-cell interaction, and stimulation of inflammatory mediator and immune cell chemoattractant secretion. Additionally, IL-17A may have a negative impact on barrier integrity as indicated by ZO-1 downregulation.


Gastroenterology Research and Practice | 2010

The Effect of Glucagon-Like Peptide-2 Receptor Agonists on Colonic Anastomotic Wound Healing

Heather Redstone; William D. Buie; David A. Hart; Laurie E. Wallace; Pamela J. Hornby; Sarah Sague; Jen J. Holst; David L. Sigalet

Background. Glucagon-like peptide 2 (GLP-2) is an intestinal specific trophic hormone, with therapeutic potential; the effects on intestinal healing are unknown. We used a rat model of colonic healing, under normoxic, and stress (hypoxic) conditions to examine the effect of GLP-2 on intestinal healing. Methods. Following colonic transection and reanastomosis, animals were randomized to one of six groups (n = 8/group): controls, native GLP-2, long-acting GLP-2 (GLP-2- MIMETIBODY, GLP-2-MMB), animals were housed under normoxic or hypoxic (11%  O2) conditions. Animals were studied five days post-operation for anastomotic strength and wound characteristics. Results. Anastomotic bursting pressure was unchanged by GLP-2 or GLP-2-MMB in normoxic or hypoxic animals; both treatments increased crypt cell proliferation. Wound IL-1β increased with GLP-2; IFNγ with GLP-2 and GLP-2-MMB. IL-10 and TGF-β were decreased; Type I collagen mRNA expression increased in hypoxic animals while Type III collagen was reduced with both GLP-2 agonists. GLP-2 MMB, but not native GLP-2 increased TIMP 1-3 mRNA levels in hypoxia. Conclusions. The effects on CCP, cytokines and wound healing were similar for both GLP-2 agonists under normoxic and hypoxic conditions; anastomotic strength was not affected. This suggests that GLP-2 (or agonists) could be safely used peri-operatively; direct studies will be required.


Journal of Molecular Recognition | 2012

The dimerization of glucagon-like peptide-2 MIMETIBODY™ is linked to leucine-17 in the glucagon-like peptide-2 region†

Audrey Baker; Sarah Sague; Tami L. R. Grygiel; Albert Schmidt; Alison Rogers; Haiyan Jiang; Marian Kruszynski; Tom Nesspor

Glucagon‐like peptide‐2 (GLP‐2) is a member of the glucagon multigene family that is produced by intestinal enteroendocrine cells in response to food intake. GLP‐2 stimulates growth of the intestinal epithelium, enhances its barrier functions, and increases nutrient uptake. Therefore, a GLP‐2 agonist may be efficacious in human diseases characterized by malabsorption or injury to the gastrointestinal epithelium. MIMETIBODY™ refers to a proprietary scaffold developed to extend the half‐life of rapidly cleared peptides. It consists of a peptide linked to a scaffold that contains sequence elements from a human immunoglobulin G including those that allow recycling through the FcRn. The GLP‐2 sequence was engineered into the MIMETIBODY™ scaffold. The primary state of both GLP‐2 and the GLP‐2 MIMETIBODY™ in DPBS was a noncovalently associated dimer indicative of self‐interaction. The increased heterogeneity and the decreased lot‐to‐lot reproducibility caused by the self‐interaction of therapeutic proteins are a challenge to drug development. A similar protein, GLP‐1 MIMETIBODY™, contains the related GLP‐1 peptide and does not form a dimer under similar conditions. Therefore, to minimize or abrogate dimerization, several variants were made by substituting GLP‐2 amino acids with the corresponding amino acids from GLP‐1. Molecular weight and secondary structure analyses reveal that substituting leucine for glutamine at position 17 (L17Q) reduces dimerization and α‐helix content yet retains bioactivity. Copyright


Archive | 2008

Methods and compositions for treating fibrosis related disorders using il-17 antagonists

Paul L. Dudas; Sarah Sague; M. Merle Elloso


Archive | 2007

GLP-2 Mimetibodies, Polypeptides, Compositions, Methods and Uses

Audrey Baker; Beverly A Moore; Thomas C. Nesspor; Karyn O'neil; Jeffrey M. Palmer; Kristen Picha; Sarah Sague


Nephron Experimental Nephrology | 2011

Contents Vol. 117, 2011

Shigeru Inomata; Minoru Sakatsume; Yuichi Sakamaki; Xingzhi Wang; Shin Goto; Tadashi Yamamoto; Paul L. Dudas; Sarah Sague; M. Merle Elloso; Francis X. Farrell; Fumitake Gejyo; Ichiei Narita; Nicole Graf; Stephen I. Alexander; David C.H. Harris; Jacqueline K. Phillips; Gopala K. Rangan; Ikko Ohara; Mitsuo Tanimoto; Tomohito Gohda; Takahiko Yamazaki; Shinji Hagiwara; Maki Murakoshi; Tatsuya Aoki; Hitoe Toyoda; Yuji Ishikawa; Kazuhiko Funabiki; Satoshi Horikoshi; Yasuhiko Tomino; Kristina G. Schwensen


Nephron Experimental Nephrology | 2011

Subject Index Vol. 117, 2011

Shigeru Inomata; Minoru Sakatsume; Yuichi Sakamaki; Xingzhi Wang; Shin Goto; Tadashi Yamamoto; Paul L. Dudas; Sarah Sague; M. Merle Elloso; Francis X. Farrell; Fumitake Gejyo; Ichiei Narita; Nicole Graf; Stephen I. Alexander; David C.H. Harris; Jacqueline K. Phillips; Gopala K. Rangan; Ikko Ohara; Mitsuo Tanimoto; Tomohito Gohda; Takahiko Yamazaki; Shinji Hagiwara; Maki Murakoshi; Tatsuya Aoki; Hitoe Toyoda; Yuji Ishikawa; Kazuhiko Funabiki; Satoshi Horikoshi; Yasuhiko Tomino; Kristina G. Schwensen


The FASEB Journal | 2009

Pro-inflammatory / Pro-fibrotic effects of Interleukin-17A on human proximal tubule epithelium

Paul L. Dudas; Sarah Sague; M. Merle Elloso; Francis X. Farrell

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Pamela J. Hornby

Louisiana State University

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