ABSTRACT
BACKGROUND AND AIM: E6011 is a humanized monoclonal antibody targeting fractalkine (FKN), a CX3C chemokine, which regulates leukocyte trafficking during inflammation. We evaluated the safety and pharmacokinetic profile of E6011 in patients with Crohn's disease (CD) and also performed preliminary pharmacodynamic (PD) and efficacy assessments. METHODS: This study included a 12-week multiple ascending dose (MAD) phase (2, 5, 10, and 15 mg/kg intravenously every 2 weeks, n = 6, 8, 7, and 7, respectively) and a 40-week Extension phase (n = 12) at the same dose as the MAD phase. Serum E6011, serum total FKN (free soluble FKN and E6011-FKN complex) as a PD marker and CD activity index were evaluated. The primary outcome was safety assessment in the MAD phase. RESULTS: Twenty-seven (96%) of 28 patients had previously been treated with anti-tumor necrosis factor α agents. During the MAD phase, adverse events (AEs) occurred in 18 (64%). The most common AE was nasopharyngitis (five patients, 18%). No severe AEs occurred. Serious AEs occurred in three patients, progression of CD in two, and anemia in one. Serum E6011 concentrations increased dose-dependently after infusion and reached a plateau around 4-6 weeks. Serum total FKN rose simultaneously. Five (18%) patients developed anti-E6011 antibodies during the study. Overall, clinical response and clinical remission were observed at Week 12 in 40% (10/25) and 16% (4/25) of active CD patients, respectively. CONCLUSION: E6011 was well-tolerated and might be effective in CD patients. These findings need to be clarified in a randomized controlled study.
Subject(s)
Antibodies, Monoclonal, Humanized , Antirheumatic Agents , Crohn Disease , Adult , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antibodies, Monoclonal, Humanized/therapeutic use , Antirheumatic Agents/adverse effects , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/therapeutic use , Crohn Disease/drug therapy , Crohn Disease/immunology , Dose-Response Relationship, Drug , Female , Humans , Immunologic Tests , Male , Middle Aged , Treatment Outcome , Young AdultABSTRACT
1. E3040 (6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl)benzothiazole), is a novel dual inhibitor of 5-lipoxygenase (5-LOX) and thromboxane synthase (Tx synthase). Here, we examined the effects of E3040 sulphate, a sulphate conjugate of E3040, on these enzyme activities in cell-free systems and on the thromboxane A2 (TxA2)-mediated Cl- secretion induced by platelet-activating factor (PAF) in isolated rat colons. 2. E3040 sulphate inhibited Tx synthase activity in a concentration-dependent manner (IC50=0.013 microM), whereas it induced little effects on 5-LOX and cyclo-oxygenase activities (IC50>100 microM) with the cell-free enzyme assay. 3. With isolated rat colonic mucosa, E3040 sulphate in a concentration-dependent manner (IC50=1.8 microM) inhibited the Cl- secretion induced by 10 microM PAF. On the other hand, E3040 sulphate (30 microM) induced no effect on the prostaglandin E2 (0.5 microM)- and leukotriene D4 (1 microM)-induced Cl- secretion in the colon. 4. PAF (10 microM) increased a release of TxB2, a stable metabolite of TxA2, from the colonic mucosa. This increase was significantly inhibited by subsequent addition of E3040 sulphate (30 microM). 5. Probenecid (100 microM), an inhibitor of organic anion transporter, abolished the inhibitory effect of E3040 sulphate on the PAF-induced Cl- secretion. Another inhibitor, sulphobromophthalein (30 microM) partially but significantly attenuated the effect of E3040 sulphate. p-aminohippuric acid (1 mM) had no effect. 6. These findings suggest that E3040 sulphate is a novel Tx synthase inhibitor, and that E3040 sulphate taken up into the colonic cells by organic anion transporters inhibits the PAF-induced Cl- secretion by blocking a release of TxA2.
