Electronic Endoscopy in Endoscopic Mucosal Resection (EMR) of Gastric Cancer

The role in which electronic endoscopy plays is important in EMR. It is useful in diagnosis and treatment of gastric cancer from a clinical viewpoint. EMR with use of electronic endoscopy allows better coordination between the operator and assistants, and thus improves the results further

XOMA 052, a potent, high-affinity monoclonal antibody for the treatment of IL-1β-mediated diseases

Interleukin-1β (IL-1β) is a potent mediator of inflammatory responses and plays a role in the differentiation of a number of lymphoid cells. In several inflammatory and autoimmune diseases, serum levels of IL-1β are elevated and correlate with disease development and severity. The central role of the IL-1 pathway in several diseases has been validated by inhibitors currently in clinical development or approved by the FDA. However, the need to effectively modulate IL-1β-mediated local inflammation with the systemic delivery of an efficacious, safe and convenient drug still exists. To meet these challenges, we developed XOMA 052 (gevokizumab), a potent anti-IL-1β neutralizing antibody that was designed in silico and humanized using Human Engineering™ technology. XOMA 052 has a 300 femtomolar binding affinity for human IL-1β and an in vitro potency in the low picomolar range. XOMA 052 binds to a unique IL-1β epitope where residues critical for binding have been identified. We have previously reported that XOMA 052 is efficacious in vivo in a diet-induced obesity mouse model thought to be driven by low levels of chronic inflammation. We report here that XOMA 052 also reduces acute inflammation in vivo, neutralizing the effect of exogenously administered human IL-1β and blocking peritonitis in a mouse model of acute gout. Based on its high potency, novel mechanism of action, long half-life and high affinity, XOMA 052 provides a new strategy for the treatment of a number of inflammatory, autoimmune and metabolic diseases in which the role of IL-1β is central to pathogenesis

Improved glucose metabolism in vitro and in vivo by an allosteric monoclonal antibody that increases insulin receptor binding affinity.

Previously we reported studies of XMetA, an agonist antibody to the insulin receptor (INSR). We have now utilized phage display to identify XMetS, a novel monoclonal antibody to the INSR. Biophysical studies demonstrated that XMetS bound to the human and mouse INSR with picomolar affinity. Unlike monoclonal antibody XMetA, XMetS alone had little or no agonist effect on the INSR. However, XMetS was a strong positive allosteric modulator of the INSR that increased the binding affinity for insulin nearly 20-fold. XMetS potentiated insulin-stimulated INSR signaling ∼15-fold or greater including; autophosphorylation of the INSR, phosphorylation of Akt, a major enzyme in the metabolic pathway, and phosphorylation of Erk, a major enzyme in the growth pathway. The enhanced signaling effects of XMetS were more pronounced with Akt than with Erk. In cultured cells, XMetS also enhanced insulin-stimulated glucose transport. In contrast to its effects on the INSR, XMetS did not potentiate IGF-1 activation of the IGF-1 receptor. We studied the effect of XMetS treatment in two mouse models of insulin resistance and diabetes. The first was the diet induced obesity mouse, a hyperinsulinemic, insulin resistant animal, and the second was the multi-low dose streptozotocin/high-fat diet mouse, an insulinopenic, insulin resistant animal. In both models, XMetS normalized fasting blood glucose levels and glucose tolerance. In concert with its ability to potentiate insulin action at the INSR, XMetS reduced insulin and C-peptide levels in both mouse models. XMetS improved the response to exogenous insulin without causing hypoglycemia. These data indicate that an allosteric monoclonal antibody can be generated that markedly enhances the binding affinity of insulin to the INSR. These data also suggest that an INSR monoclonal antibody with these characteristics may have the potential to both improve glucose metabolism in insulinopenic type 2 diabetes mellitus and correct compensatory hyperinsulinism in insulin resistant conditions

Metabolic profile of diet induced obesity mice treated with XMetS and controls.

<p>At the end of the 4-week study with diet induced obesity mice, the animals were fasted 14 hours, weighed and plasma was obtained to determine the above parameters. Mice (n = 10/group) were treated with antibody at 10 mg/kg, twice weekly. Values are shown as mean ± SEM. *p<0.05 vs. diabetic+control IgG.</p

Metabolic profile of multi-low dose, streptozotocin/high-fat diet mice treated with XMetS and controls<b>.</b>

<p>At the end of the 6-week study with multi-low dose, streptozotocin/high-fat diet mice, the animals were fasted 14 hours, weighed and plasma was obtained to determine the above parameters. Mice (n = 8/group) were treated with antibody at 10 mg/kg, twice weekly. Values are shown as mean ± SEM. *p<0.05 vs. diabetic+control IgG.</p

XMetS improves glucose metabolism in multi-low dose, streptozotocin/high-fat diet mice.

<p><b>A–C.</b> ICR multi-low dose, streptozotocin/high-fat diet mice were treated twice weekly with either control antibody (10 mg/kg) or XMetS (10 mg/kg). Age-matched non-diabetic ICR mice were treated twice weekly with control antibody (10 mg/kg). <b>A</b>. Blood glucose levels were obtained weekly for six weeks following a 14-hour fast. <b>B</b>. After five weeks of treatment and following a 4-hour fast, insulin was administered intraperitoneally (0.75 U/kg) and blood glucose levels were obtained for an additional 120 minutes. <b>C</b>. After three weeks of treatment and following a 14-hour fast, a glucose bolus was administered intraperitoneally (1 g/kg) and blood glucose levels were measured for 120 minutes. Mean ± SEM are shown (n = 8 mice/group).</p

XMetS binds to the A and B isoforms of the INSR with high affinity.

<p>CHO cells expressing either the B or A isoform of the hINSR, and parental CHO cells were preincubated for 10 minutes at 4°C in the presence of 100 nM insulin followed by a 120 minute incubation at 15°C with increasing concentrations of XMetS. XMetS binding to the INSR was measured by FACS. Mean of duplicate determinations are shown.</p