Open-label, dose escalation phase I study in healthy volunteers to evaluate the safety and pharmacokinetics of a human monoclonal antibody to Clostridium difficile toxin A.

BACKGROUND: Recent data suggest that Clostridium difficile-associated diarrhea is becoming more severe and difficult to treat. Antibody responses to C. difficile toxin A are protective against symptomatic disease and recurrence. We examined the safety and pharmacokinetics (pk) of a novel neutralizing human monoclonal antibody against C. difficile toxin A (CDA1) in healthy adults. METHODS: Five cohorts with 6 subjects each received a single intravenous infusion of CDA1 at escalating doses of 0.3, 1, 5, 10, and 20 mg/kg. Safety evaluations took place on days 1, 2, 3, 7, 14, 28, and 56 post-infusion. Samples for pk analysis were obtained before and after infusion, and at each safety evaluation. Serum CDA1 antibody concentrations and human anti-human antibody (HAHA) titers were measured with enzyme-linked immunosorbent assays. A noncompartmental model was used for pk analysis. RESULTS: Thirty subjects were enrolled. The median age was 27.5 yrs. There were no serious adverse events (AE) related to CDA1. Twenty-one of the 48 reported non-serious adverse events were possibly related to CDA1, and included transient blood pressure changes requiring no treatment, nasal congestion, headache, abdominal cramps, nausea, and self-limited diarrhea. Serum CDA1 concentrations increased with escalating doses: mean C(max) ranged from 6.82 microg/ml for the 0.3 mg/kg cohort to 511 microg/ml for the 20 mg/kg cohort. The geometric mean values of the half-life of CDA1 ranged between 25.3 and 31.8 days, and the volume of distribution approximated serum. No subject formed detectable HAHA titers. CONCLUSION: Administration of CDA1 as a single intravenous infusion was safe and well tolerated. C(max) increased proportionally with increasing doses. A randomized study of CDA1 in patients with C. difficile associated diarrhea is underway.

Association between IgG2 and IgG3 subclass responses to toxin A and recurrent Clostridium difficile-associated disease.

BACKGROUND & AIMS: Individuals who mount a significant serum immunoglobulin (Ig)G response to toxin A are protected against recurrent Clostridium difficile-associated disease (CDAD). We investigated whether humoral immune deficiencies and/or specific IgG subclass responses are associated with recurrent CDAD. METHODS: We compared the clinical characteristics and humoral immune responses of 13 patients with recurrent CDAD with 13 matched controls with a single CDAD episode. We measured the serum IgG titers to tetanus and diphtheria toxoids, as well as total and toxin A- and toxin B-specific serum IgG, IgA, and IgG subclass concentrations. RESULTS: There were no differences between the single and recurrent CDAD subjects in terms of age, sex, ethnicity, or other potential confounding variables. The total duration of diarrhea in patients with recurrent CDAD was greater (median, 62 vs 17 days; P = .005). IgG titers to tetanus and diphtheria toxoids, total IgG, and IgG subclass levels were similar in both groups. The total IgA was somewhat lower in those with recurrent CDAD (204 vs 254 mg/dL; P = .05). IgA, IgG, IgG1, and IgG4 anti-toxin A and anti-toxin B levels were similar in both groups. However, IgG2 and IgG3 anti-toxin A levels were significantly lower in the recurrent group (P = .01 and .001, respectively). CONCLUSIONS: Subjects with recurrent CDAD did not show evidence of widespread humoral immune deficiency or of IgG subclass deficiency. Their low serum IgG anti-toxin A concentrations reflected selectively reduced IgG2 and IgG3 subclass responses. Measurement of specific IgG2/3 anti-toxin A may be useful in selecting patients for treatment with agents to prevent recurrent CDAD.