Diane Marshall

A Short Treatment With an Antibody to Sclerostin Can Inhibit Bone Loss in an Ongoing Model of Colitis

Chronic inflammation leads to bone loss, and increased fracture rates have been reported in a number of human chronic inflammatory conditions. The study reported here investigates the skeletal effects of dosing a neutralizing antibody to the bone regulatory protein sclerostin in a mouse model of chronic colitis. When dosed prophylactically, an antibody to sclerostin (Scl‐AbI) did not reduce the weight loss or histological changes associated with colitis but did prevent inflammation‐induced bone loss. At the end of the experiment, Scl‐AbI–treated animals had a significantly higher femoral BMD (+27%, p < 0.05) than control antibody (Cntrl‐Ab)‐treated animals. In a second experiment, treatment with Scl‐AbI was delayed until colitis had developed, by which time the mechanical properties of femurs in colitic animals were significantly worse than those of healthy age‐matched control mice (maximum load, −26%, p < 0.05; energy, −37%, p < 0.05; ultimate strength, −33%, p < 0.05; elastic modulus, −17%, p < 0.05). A short treatment with Scl‐AbI halted bone loss and reversed the decline of both intrinsic and extrinsic mechanical properties of the femur such that, after 19 days of treatment, the bone mechanical properties in the Scl‐AbI–treated animals were not significantly different from those of noncolitic age‐matched controls. Serum markers of bone formation and resorption suggested that the antibody to sclerostin stimulated osteoblast activity and inhibited osteoclast‐mediated bone resorption.

Blockade of colony stimulating factor‐1 (CSF‐1) leads to inhibition of DSS‐induced colitis

Background Intestinal inflammation associated with inflammatory bowel disease (IBD) is typically characterized by an inflammatory cell infiltrate and pro‐inflammatory cytokine production. Of particular interest, the frequency of colony stimulating factor‐1 (CSF‐1)‐expressing cells is increased in active lesions. In this study, we have investigated the role of CSF‐1 in mucosal inflammation, using a murine model of colitis induced by dextran sulfate sodium (DSS). Methods A neutralizing anti‐CSF‐1 antibody was administered to Balb/c mice that received DSS in their drinking water. Signs of colitis, such as clinical disease score, cellular infiltrate, and cytokine production, were assessed. Results Administration of a neutralizing anti‐CSF‐1 antibody significantly inhibited DSS‐induced colitis. Clinical symptoms, such as weight loss and the appearance of diarrhea or fecal blood, were reduced by CSF‐1 blockade; histologic scores were also improved. The cellular infiltrate of macrophages and T cells was inhibited and a trend toward reduced production of pro‐inflammatory cytokines was noted. Conclusions This is the first study to demonstrate that CSF‐1 plays an important role in mediating intestinal mucosal inflammation and therefore may prove to be an attractive therapeutic target for intestinal diseases such as inflammatory bowel disease. (Inflamm Bowel Dis 2006)

Discovery and characterization of olokizumab: a humanized antibody targeting interleukin-6 and neutralizing gp130-signaling.

Interleukin-6 (IL-6) is a critical regulator of the immune system and has been widely implicated in autoimmune disease. Here, we describe the discovery and characterization of olokizumab, a humanized antibody to IL-6. Data from structural biology, cell biology and primate pharmacology demonstrate the therapeutic potential of targeting IL-6 at “Site 3”, blocking the interaction with the signaling co-receptor gp130.

OX40 blockade inhibits house dust mite driven allergic lung inflammation in mice and in vitro allergic responses in humans

The costimulatory receptor OX40 is expressed on activated T cells and regulates T‐cell responses. Here, we show the efficacy and mechanism of action of an OX40 blocking antibody using the chronic house dust mite (HDM) mouse model of lung inflammation and in vitro HDM stimulation of cells from HDM allergic human donors. We have demonstrated that OX40 blockade leads to a reduction in the number of eosinophils and neutrophils in the lavage fluid and lung tissue of HDM sensitized mice. This was accompanied by a decrease in activated and memory CD4+ T cells in the lungs and further analysis revealed that both the Th2 and Th17 populations were inhibited. Improved lung function and decreased HDM‐specific antibody responses were also noted. Significantly, efficacy was observed even when anti‐OX40 treatment was delayed until after inflammation was established. OX40 blockade also inhibited the release of the Th2 cytokines IL‐5 and IL‐13 from cells isolated from HDM allergic human donors. Altogether, our data provide evidence of a role of the OX40/OX40L pathway in ongoing allergic lung inflammation and support clinical studies of a blocking OX40 antibody in Th2 high severe asthma patients.

SAT0076 Comparison of anti-interleukin-6 and anti-interleukin-6 receptor antibodies using in vivo functional systems

Background The multi-step assembly of the interleukin-6 (IL-6) signaling complex offers the potential for several therapeutic points of intervention in the treatment of rheumatoid arthritis; for example, targeting the cytokine IL-6, the IL-6 receptor (IL-6R; gp80), or gp130. Objectives The objective of this study was to compare affinity-matched anti-murine monoclonal antibodies (mAbs) that target either the IL-6 cytokine or the IL-6 receptor in a range of in vivo assays. Methods Affinity-matched anti-murine reagents 54E07 mAb (anti-IL-6) and 440-1 mAb (anti-IL-6R; gp80) were evaluated for their ability to inhibit either murine IL-6 or CFA-induced serum amyloid A (SAA). IL-6 is also known to have a significant role in B-cell function; therefore, these antibodies (Abs) were evaluated for their ability to inhibit dinitrophenyl (DNP)-specific Ab production. Furthermore, these Abs were dosed to steady state and their capacity to inhibit collagen-induced arthritis (CIA) in DBA-1 mice was evaluated. Results 54E07 mAb produced a ≥90% reduction in the SAA response to both IL-6 and CFA at a dose of 0.1 mg/kg (p<0.01 and p<0.001, respectively). In contrast, doses of at least 1 mg/kg and 3 mg/kg of 440-1 mAb were required to significantly reduce the SAA response (p<0.001 for both doses). In vivo inhibition of IL-6 by 54E07 mAb significantly reduced the DNP-specific IgG response by 72% at doses as low as 0.3 mg/kg s.c. (p<0.05), whereas 440-1 mAb only achieved a significant reduction (80%) in DNP-specific Ab titer at a dose of 10 mg/kg s.c. (p<0.05). In the murine CIA model, both 54E07 mAb and 440-1 mAb achieved a similar reduction (≥97%) in the clinical arthritis score at the same high dose exposure; however, at the same low dose exposure, only 54E07 mAb caused a significant reduction (67%) in clinical score versus controls. Conclusions These murine in vivo studies strongly suggest that targeting IL-6 cytokine rather than the IL-6 receptor is the more efficient therapeutic approach for the treatment of autoimmune diseases such as rheumatoid arthritis. Disclosure of Interest None Declared