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Immunogenicity of Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF) Products in Patients Undergoing Combination Therapy with GM-CSF¹

Division of Immunobiology, National Institute for Biological Standards and Control, Hertfordshire EN6 3QG, United Kingdom [M. W., C. B., R. G-D., R. T.], and Department of Oncology, Karolinska Hospital, Stockholm 17176, Sweden [A-L. H. S., P. R., M. L., H. M.]

In this study, we have assessed the development of neutralizing and nonneutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in two groups of patients with metastatic colorectal carcinoma receiving two different GM-CSF products. Three clinical trials were carried out, and a combination of GM-CSF and a colon carcinoma-reactive antibody was used in the absence of any concomitant chemotherapy. Two different GM-CSF products, both rDNA-derived and produced in Escherichia coli, were used. Patients in Trial 1 received product X, and those in Trials 2 and 3 received product Y. Patients in Trial 2 also received interleukin 2 in an attempt to potentiate immune responses. After the first cycle of treatment, no GM-CSF antibodies were detected, but on subsequent therapy, 28 of the 38 patients tested receiving product Y (Trials 2 and 3) developed antibodies that bound to the GM-CSF product used for therapy. However, none of the patients developed antibodies that neutralized the biological activity of GM-CSF, as assessed using an in vitro bioassay. Furthermore, there was no in vivo impairment in GM-CSF-induced expansion of leukocytes, neutrophils, and eosinophils in the patients. In contrast, 19 of the 20 patients given product X (Trial 1) developed GM-CSF binding antibodies, and 9 of these patients were shown to develop antibodies that neutralized the biological activity of GM-CSF. The presence of the latter was associated with a significant reduction in GM-CSF-induced expansion of leukocytes, neutrophils, and eosinophils in patients. Therefore, product X appears to be more immunogenic than product Y. Immunochemical characterization confirmed that the specificity of the antibody responses varied depending on the product used for therapy. Whereas sera from Trial 1 patients treated with product X showed the presence of antibodies with strong recognition of GM-CSF proteins, sera from patients treated with product Y showed varied recognition of GM-CSF ranging from fairly strong to very weak but bound predominantly to two E. coli-derived, non-GM-CSF-related proteins of M_r 20,000 and M_r 30,000. Therefore, in sera from patients receiving product Y, the antibody specificity appeared to be directed not only against GM-CSF but also against non-product-related host cell contaminants. This study shows that GM-CSF products used for therapy are potentially immunogenic and generate antibodies to GM-CSF and/or other non-product-related contaminants. However, only antibodies that neutralize the biological activity of GM-CSF compromise therapeutic efficacy of the cytokine.

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