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Alteration of Interleukin 2 (IL-2) Pharmacokinetics and Function by IL-2 Antibodies Induced after Treatment of Colorectal Carcinoma Patients with a Combination of Monoclonal Antibody 17-1A, Granulocyte Macrophage Colony-Stimulating Factor, and IL-2¹

Department of Oncology (Radiumhemmet) [A-L. H. S., P. R., H. M.] and Immune and Gene Therapy Laboratory, Cancer Centre Karolinska [B. G., P. R., H. M.], Karolinska Hospital, SE-171 71 Stockholm, Sweden; Division of Immunobiology, National Institute for Biological Standards and Control, Potters Bar, Herts ENG 3QG, United Kingdom [M. W., C. B., R. T.]; and Laboratory of Hematology, Kliniskt Forskningscentrum, Novum, Huddinge University Hospital, SE-14186 Stockholm, Sweden [M. H.]

In this study, we have assessed the development of neutralizing and non-neutralizing interleukin 2 (IL-2) antibodies in metastatic colorectal carcinoma patients receiving a colon carcinoma reactive monoclonal antibody (17-1A) in combination with granulocyte macrophage colony-stimulating factor and IL-2 therapy. Before treatment, no IL-2 antibodies were detected in any of the patients. After therapy, 10 of the 19 patients tested developed antibodies that bound to the IL-2 product used for therapy, but only one developed antibodies that neutralized the biological activity of IL-2 as assessed using an in vitro bioassay. We found that the induction of IL-2 antibodies in some patients irrespective of their neutralizing potential had a significant impact on IL-2 pharmacokinetics. A significant reduction of the area under the concentration-time curve and maximum concentration (C_max) and increased IL-2 distribution and clearance were observed in IL-2 antibody-positive patients in comparison with IL-2 antibody-negative patients. A significant decrease in IL-2-mediated expansion of lymphocytes was also evident in patients positive for IL-2 antibodies in comparison with those negative for these antibodies. Further characterization of sera from patients with antibodies showed that, in most cases, the antibodies recognized different IL-2 preparations. Results also showed that serum IL-2 concentration at initiation of therapy in patients was significantly higher relative to healthy control donors. The endogenous production of IL-2 gradually increased during the treatment cycles. To conclude, induction of neutralizing and non-neutralizing antibodies in cytokine-treated patients should be carefully monitored in terms of their clinical significance.

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