Abstract 150: Trastuzumab-Associated Inflammatory Responses in Healthy Volunteers: Possible Insights in Immunogenicity of Monoclonal Antibodies
Many monoclonal antibodies are associated with an inflammatory reaction. For example, trastuzumab induces such a response in 40-60% of treated patients, most often after the first administration. Apart from causing discomfort for the patient, these responses may increase the risk of antibody formation against the therapeutic agent. Not much is known on the pathways involved, however, comparing clinical findings and results of in vitro cytokine release between subjects who did and did not develop an inflammatory reaction may offer guidance for further investigations.
A cohort of 54 healthy male volunteers randomly received either placebo (n=8) or 6 mg/kg trastuzumab (n=46) intravenously in 90 minutes. Adverse events were captured and regular safety assessments were performed, consisting of vital signs and routine clinical laboratory tests. In addition, whole blood from a selection of volunteers with clinical signs of an inflammatory reaction as well as whole blood from trastuzumab-naïve healthy volunteers was incubated in vitro with trastuzumab.
Fever was observed in 9 (19.6%) volunteers receiving trastuzumab, occurring in combination with other influenza-like symptoms in 4. Seven subjects reached a temperature of ≥38.5°C, and four ≥39.0°C, with a maximum of 39.4°C. One volunteer developed influenza-like illness without fever. The mean latency between the onset of complaints and start of infusion was 4.7 h (SD 2.6). The fever was accompanied by a mean increase in leucocytes of 54% (SD 31), predominantly neutrophils (increase 128%, SD 60), at 24 h post administration. Although differences in baseline characteristics were not observed, a rise in neutrophils (mean increase at 24 h 94%, SD 55) and body temperature (mean peak value 37.3°C, SD 0.4) was also noted in the 37 subjects who did not develop fever. None of the placebo treated volunteers displayed this phenomenon.
These results suggest that 6 mg/kg trastuzumab is capable of inducing an inflammatory response, although the magnitude and thus the clinical manifestations differ between subjects. Data on the correlation between in vitro cytokine release, which might serve as a platform for immunogenicity research, and the observed clinical response will be presented.
Author Disclosures: J.A.A. Reijers: None. M. Moerland: None. J. Burggraaf: None.
- © 2014 by American Heart Association, Inc.