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Biotech / Medical : Indications -- Psoriasis/Chronic Inflammation -- Ignore unavailable to you. Want to Upgrade?

To: Icebrg who wrote (406)	5/15/2003 6:10:57 PM
From: Icebrg	Read Replies (1) \| Respond to of 631

Efficacy and Safety of a Humanized α4β7 Antibody in Active Crohn's Disease (CD) Brian G. Feagan, Gordon Greenberg, Gary Wild, John W. D. McDonald, Richard Fedorak, Pierre Pare, Kei Kishimoto, Jose-Carlos Gutierrez-Ramos, Julie Krop [This is the MLN02 Crohn's abstract. It appears that they might have used too low a dose]. Selective blockade of leukocyte-vascular endothelium interactions is a promising strategy for the treatment of IBD. The α4β7 integrin is an adhesion molecule that mediates selective recruitment of lymphocytes to the gut. Its ligand, MadCaM, is almost exclusively expressed in the intestinal vascular endothelium. We evaluated the efficacy, pharmacokinetics, and safety of MLN-02, a humanized monoclonal antibody directed against α4β7 in patients with mild-moderately active CD. Methods: 185 patients were enrolled in a double-blind, placebo controlled, dose-finding trial. Eligible patients (CDAI > 220, receiving a stable dose of 5-ASA or antibiotics or no medical therapy for CD) were randomized to receive placebo, 0.5 mg/kg, or 2.0 mg/kg MLN-02 administered intravenously on Days 1 and 29. Disease activity was assessed by CDAI score on Day 57 (remission = CDAI £150, response = CDAI decrease ³70 points). Pharmacokinetic and pharmacodynamic (saturation of α4β7 on peripheral blood lymphocytes- PBLs) assessments were obtained from a 30 patient subset. Results: Remission rates were: placebo- 20.7%, 0.5 mg/kg- 29.5% (placebo vs. 0.5 mg/kg p=0.30) and 2.0 mg/kg- 36.9% (placebo vs. 2.0 mg/kg p=0.04) whereas the corresponding response rates were 41.4%, 49.2% (placebo vs. 0.5mg/kg p=0.36), and 53.1% (placebo vs. 2.0 mg/kg p=0.14) Pharmacokinetic data indicated the antibody had a half-life of approximately 12 days. Pharmacodynamic data suggested that complete saturation of α4β7 was not achieved over the duration of treatment. Subgroup analysis showed that patients who obtained consistent and sustained saturation of α4β7 on PBLs were more likely to enter remission than those who did not. No important differences in adverse events were noted among the three treatment groups. Conclusion MLN-02, administered at 2 .0 mg/kg, is a biologically active therapy for the treatment of active CD. Future trials to evaluate higher doses of mln02 and the relation of higher doses to sustained saturation are under consideration.

To: Icebrg who wrote (406)	6/14/2003 1:07:13 PM
From: scaram(o)uche	Read Replies (1) \| Respond to of 631

>> Now we need the help from Rick << Finally getting around to catching up with this thread. I'm about 30 messages behind....... Dose response issues..... first, I'd say that biopsy-negative data is sparse, and that we shouldn't worry too much about the inverse dose response. The story is still "way out". We also don't know if anti-integrin is merely passively covering an epitope that is critical to migration or inducing a CHANGE in the lymphocyte which reduces its capacity to migrate. (please correct me if data relevant to this issue is "out there" and conclusive, I'm behind.) Lack of dose response..... there are two different ways to look at "saturation" binding. One is when all available (or nearly) antigen on the cell is bound by antibody. Theoretically, this can occur for integrins at a molar ratio of 0.5, MAb:integrin. Under these conditions, cross linking occurs.......... one antibody can bind to two integrin molecules. As you increase the concentration of antibody, you increase the frequency with which one Fab is bound to integrin and the other is free. Under these conditions, integrin cross-linking is lower but "antigen saturation" is still complete. If the mechanism of action for the MAb is merely to passively cover the migration-relevant integrin, then you would not expect a bell-shaped dose response curve. If cross-linking is required to "change" the lymphocyte via integrin-mediated signaling, then higher doses of MAb will be less effective than some lower ones. Remember..... the ligands are on a cell surface are effectively immobilized relative to a soluble MAb. The immobilized ligand can act like an antibody to bring intracellular domains of integrins into proximity. Who would one ask to get a better grip on this sort of stuff, apart (perhaps) from (some) senior scientists at BGEN, ELN and MLNM? Jeff Ledbetter........... seattletimes.nwsource.com Ed Clark.......... ncbi.nlm.nih.gov These are two guys who think correctly. BTW, do you know Anders Orn at Karolinska, an old friend?