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The Human Antimouse Immunoglobulin Response and the Anti-idiotypic Network Have No Influence on Clinical Outcome in Patients with Minimal Residual Colorectal Cancer Treated with Monoclonal Antibody CO17–1A

Institut für Immunologie der Ludwig-Maximilians-Universität München, 80336 Munich, Germany [R. G., G. R.]; University Hospital Leiden, 2300 RC Leiden, the Netherlands [L. J. M. v. H., S. O. W.]; and Amgen GmbH, 80992 Munich Germany [E. H.]

Murine monoclonal antibodies (mAbs), when administered to patients, induce a human antimouse immunoglobulin immune response, especially when multiple infusions are required to obtain therapeutic efficacy. In a randomized Phase II clinical study, 83 patients with colorectal carcinoma of stage Dukes C were treated with the murine IgG2a mAb 17–1A (ab1) after curative surgery. The regimen consisted of a single infusion of 500mg of 17–1A within 2 weeks after surgery, followed by 100mg of mAbs four times every 4 weeks. Sera were taken every 2–3 weeks and screened for human antimouse antibodies (HAMA). HAMA were measured by a capture ELISA and an indirect antihuman immunoglobulin ELISA for the analysis of IgG and IgM isotypes. Anti-idiotypic antibodies (ab2) were detected by an inhibition ELISA, and anti-anti-idiotypic antibodies (ab3), recognizing the original antigen, were determined by flow cytometric analysis. About 20% of patients failed to develop HAMA; in the other patients, antibody titers were initially low after the first two infusions and reached their maximum only after a fifth infusion at 18–20 weeks after surgery. An analysis that differentiated between patients who developed recurrences and those who remained tumor-free did not show any difference in antibody titers between the two groups, neither for total HAMA nor for IgG, IgM, or ab2. The formation of ab3 was analyzed in eight patients and proved to be negative in all of them. HAMA remained detectable up to 2 years after the last treatment. In patients who experienced adverse events associated with therapy, HAMA titers tended to rise earlier; this difference, however, was not statistically significant. Thus, neither a beneficial nor a detrimental effect of HAMA formation could be determined for the clinical response to antibody therapy.

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