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

Beth Israel Deaconess Medical Center, University of Massachusetts Medical School, Boston, Massachusetts, USA.
Vaccine (Impact Factor: 3.62). 07/2008; 26(27-28):3404-9. DOI: 10.1016/j.vaccine.2008.04.042
Source: PubMed


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.
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.
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.
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.

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Available from: Israel Lowy, Aug 10, 2015
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    • "Passive immunization or antibody administration has been well accepted in medical practice. Various types of antibodies against viral and bacterial infection were tested in vitro, in animal models and in clinical trials (Heijtink et al. 2001; Domanski et al. 2005; Taylor et al. 2008). More recently, humanized monoclonal antibody specific to E protein of West Nile virus (WNV) has been used in phase I clinical trial. "
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    • "Passive immunotherapies for the treatment of recurrent CDI with antibodies that target the RBDs of the toxins have been tested in clinical trials. Two fully humanized monoclonal antibodies, CDA-1 and CDB-1, which target and neutralize TcdA and TcdB, respectively, in addition to standard antimicrobial therapy, were tested in 200 patients recovering from an initial episode of CDI in a phase 2 multicenter, randomized, double-blind, placebo-controlled trial.103,104 Interestingly, in a phase 1 trial, the infusion of CDA-1 alone was not protective again emphasizing the importance of neutralizing both toxins. "
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