Effects of an anti-CD5 immunoconjugate (CD5-Plus) in recent onset type I diabetes mellitus: A preliminary investigation

Abstract

Type-I (insulin-dependent) diabetes mellitus is an immunologically mediated disease that results in destruction of the insulin secreting β cells of the pancreas. T cells have been implicated in the pathogenesis of this disease. One novel form of anti-T-cell therapy is the immunoconjugate CD5-Plus®. This agent is composed of the murine IgG 1 monoclonal antibody H65, which is directed toward the CD5+ antigen; and ricin A chain, a ribosomal inhibitor protein. We performed a pilot study to evaluate the safety of the immunoconjugate in subjects with type-I diabetes mellitus. We conducted a dose-escalation study using CD5-Plus given as an intravenous infusion for 5 consecutive days. Fifteen subjects (12 men and 3 women) with a mean age of 26 years, a mean duration of diabetes of 4.8 months, and a minimum stimulated C peptide of 0.3 pmol/mL were entered. Six subjects each were treated at the 0.1 and 0.2 mg/kg/day dosage levels, and three subjects were treated at the 0.33 mg/kg/day dose. Glycemic control was determined monthly by recording the glycohemoglobin, total daily insulin requirements, and fasting blood glucoses. β-cell function was measured by determining the C-peptide response to a mixed formula meal (Sustacal®) at baseline and at 1,3,6,9, and 12 months after treatment. The area under the curve (AUC) of the C-peptide response was calculated and, to reduce variability, related to that of the same subject at baseline. An analysis of subjects who retained at least 80% of their baseline β-cell function as measured by the AUC was performed. In addition, logarithms of the normalized areas under the C-peptide curve (AUC/AUC 0) were determined, and the regression line was calculated. This line was compared to that generated by a similar analysis in historical controls who had participated in a previous study using placebo and cyclosporine. T cells were rapidly depleted during the infusion course and recovered to normal values within 30 days. No long-term adverse events were reported. The analysis of subjects retaining 80% of their initial AUC suggested a dose-dependent effect that was significant ( p < 0.05) by the Cochran-Armitage test for trend in dose response at month 12. The slope of the linear regression line for all subjects was different from zero ( p < 0.03), but this was accounted for entirely by the low-dose group. The slope of the regression line in subjects treated at the two higher doses of CD5-Plus did not significantly differ from zero and was similar to the cyclosporine-treated group of a previous study. This study demonstrates that CD5-Plus was tolerated by a group of recent onset type-I diabetic patients and resulted in reversible T-cell depletion. Preliminary efficacy analysis suggests a dose-dependent preservation of β-cell function. A full-scale, randomized, controlled trial to investigate the potential of CD5-Plus to preserve C-peptide function in new onset type-I diabetes is warranted.