A Phase 1 Open-Label, Single-Dose, Dose-Escalation Study of Mdx-1100, a High-Affinity, Neutralizing, Fully
Human Igg1? Anti-CXCL10 (Ip10) Monoclonal Antibody, in Ulcerative Colitis
[This abstract (with no further references) was posted to the Yahoo board. It is as far as I know the first reported clinical trial where anti-IP-10 has been used].
Robert Hardi, Lloyd Mayer, Stephan R. Targan, Michael Yellin, Pina M. Cardarelli, Kiron M. Das
Background:
Chemokines play key roles in regulating mucosal inflammatory cell trafficking in Crohn's disease, ulcerative colitis (UC) and other inflammatory diseases. Inhibition of the chemokine CXCL10, an IFN? induced chemokine, abrogates colitis in some murine models. Mucosal expression of CXCL10 and its cell surface receptor, CXCR3, are markedly upregulated in inflammatory bowel disease (IBD). Therefore, CXCL10 neutralization may have therapeutic potential in the treatment of IBD.
Methods:
The primary objective of this open-label, dose-escalation study was to evaluate the safety of single doses of MDX-1100 in patients with UC flaring (UCDAI of 4-9) on stable doses of standard therapy and off anti-TNF therapy for at least 8 weeks prior to the study. Cohorts of 3-6 patients were administered a single infusion of MDX-1100 at doses of 0.3, 1.0, 3.0, or 10 mg/kg and were followed for at least 70 days post infusion. Decrease in the UCDAI by = 3 points at Day 29 compared to baseline was considered a response. Responders were permitted up to 3 additional MDX-1100 infusions at the time of relapse. Peripheral blood mononuclear cells and colon biopsy specimens were studied for expression of CXCL10 and CXCL10-induced proteins. Serum anti-MDX-1100 antibody responses and MDX-1100 concentrations were determined by ECL and ELISA, respectively. This study was approved by the appropriate Investigational
Review Boards.
Results:
To date, the 0.3 (n=3), 1.0 (n=4) and 3.0 (n=4) mg/kg cohorts have been completed and the 10 mg/kg cohort (n=1) is actively enrolling. MDX-1100 has been well tolerated. No drug related adverse events have been reported. There has been 1 SAE; a patient in the 3.0 mg/kg cohort admitted to the hospital for anemia and worsening UC symptoms that necessitated colectomy. Three patients in the 1.0 mg/kg and 2 patients in the 3.0 mg/kg cohorts had clinical responses; however, the clinical response of one patient in the 1.0 mg/kg cohort was confounded by the initiation of concomitant immunomodulator therapy 2 months prior to MDX-1100 administration. Three responding patients relapsed after 50, 85 and 93 days, respectively and have been administered additional MDX-1100 doses; 2 patients responded to re-treatment. Pharmacodynamic and pharmacokinetic analyses were performed.
Conclusion:
This pilot study demonstrated that single doses of up to 10 mg/kg of a fully human anti-CXCL10 monoclonal antibody in patients with active ulcerative colitis was safe. Clinical responses were seen at dose levels at or above 1.0 mg/kg. These data support further studies of MDX-1100 in ulcerative colitis. |
