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Biotech / Medical : Cambridge Antibody Technology Group -- Ignore unavailable to you. Want to Upgrade?

To: nigel bates who wrote (480)	5/17/2004 11:25:13 AM
From: keokalani'nui	Respond to of 625

[Re: GDF-8] Biochem Biophys Res Commun. 2004 Mar 12;315(3):525-31. Related Articles, Links Characterization and identification of the inhibitory domain of GDF-8 propeptide. Jiang MS, Liang LF, Wang S, Ratovitski T, Holmstrom J, Barker C, Stotish R. MetaMorphix, Inc., Savage, MD 20763, USA. mjiang@metamorphixinc.com GDF-8 is a negative regulator of skeletal muscle mass. The mechanisms which regulate the biological activity of GDF-8 have not yet been elucidated. Analogous to the TGF-beta system, GDF-8 propeptide binds to and inhibits the activity of GDF-8. In these studies, we define the critical domain of the GDF-8 propeptide necessary for inhibitory activity. Two molecules of GDF-8 propeptide monomer inhibit the biological activity of one molecule of GDF-8 homodimer. Although the propeptide contains N-linked glycosylation when synthesized in mammalian cells, this glycosylation is not necessary for the inhibition of GDF-8. Taking advantage of the bacterial expression system, we express and purify GDF-8 propeptide which retains full inhibitory activity. To define the functional regions of the propeptide, we express a series of truncated GST-propeptide fusion proteins and examined their inhibitory activity. We observe that fusion proteins containing the C-terminal region (amino acid residues 99-266) are very stable, but do not exhibit inhibitory activity; while fusion proteins containing the N-terminal region (amino acid residues 42-115) are labile but contain essential inhibitory activity. The data suggest that the C-terminal region may play a role in the stability of the GDF-8 propeptide and that the inhibitory domain is located in the region between amino acids 42 and 115. PMID: 14975732 [PubMed - indexed for MEDLINE]

To: nigel bates who wrote (480)	5/17/2004 12:18:09 PM
From: keokalani'nui	Read Replies (1) \| Respond to of 625

Abbott Laboratories' New Investigational Anti-Interleukin-12 (IL-12) Fully Human Monoclonal Antibody Shows Positive Results in Crohn's Disease Study Monday May 17, 11:00 am ET NEW ORLEANS, May 17 /PRNewswire-FirstCall/ -- Results from a Phase II study released Monday suggest that Abbott Laboratories' (NYSE: ABT - News) ABT-874, a fully human anti-interleukin-12 monoclonal antibody, showed significant differences in response and remission rates in patients with active Crohn's disease (highest response rate 75 percent at week 7; highest remission rate 50 percent at week 19) compared to placebo in one arm of the study. ABT-874 is a new, investigational agent designed to target and neutralize IL-12, a known mediator of inflammation in Crohn's disease. The data was presented at the Digestive Disease Week annual meeting in New Orleans. "These initial data are very exciting and suggest that anti-IL-12 therapy offers promise as a new approach in biologic treatment for Crohn's," said Charles O. Elson, M.D., Professor of Medicine and Microbiology, University of Alabama at Birmingham. Trial Information Seventy-nine patients with active Crohn's disease were enrolled in a randomized, double-blind, placebo-controlled trial of ABT-874. Patients were randomly assigned to receive seven weekly subcutaneous injections of ABT-874 (1 mg/kg or 3 mg/kg or placebo) either with a four week interval between the first and second injection (Cohort 1) or with no interruption (Cohort 2). All patients were followed for 18 weeks after the final injection of study drug. Patients in Cohort 2 who received 3 mg/kg of ABT-874 showed a significant difference in response rates and remission rates compared to patients who received placebo. At the end of treatment (7 weeks), the response rate for this group was 75 percent and the remission rate was 38 percent. After 12 weeks of follow-up (week 19), 50 percent of patients were in remission with 69 percent achieving a clinical response. Participants had active Crohn's disease as indicated by a Crohn's Disease Activity Index (CDAI) score of 220-450. CDAI is a weighted composite score of eight clinical factors, including daily number of liquid or very soft stools, severity of abdominal pain, level of general well-being, presence of extraintestinal manifestations or abdominal mass, use of anti-diarrheal agents, hematocrit and decrease in standard body weight. Results were measured by changes in CDAI score. Remission was defined as a CDAI < 150 points and clinical response as a decrease in the CDAI score of greater than or equal to 100 points from baseline. The response and remission rates for patients receiving ABT-874 in Cohort 1 were not significantly different from the placebo group. In both groups, antibody-related adverse events were similar to placebo except for local injection site reactions. "We're highly encouraged with the performance of ABT-874 we have seen so far," said Elliot Chartash, M.D., global project head, Immunoscience Development, Abbott Laboratories. "These data are encouraging as we assess the potential of ABT-874 to provide benefit to patients suffering from Crohn's. We also are continuing to explore the role of anti-IL-12 therapy in other autoimmune conditions, including multiple sclerosis."