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© 1992 Oxford University Press

research-article

Immunogenic Properties of Structurally Modified Human Tissue Plasminogen Activators in Chimpanzees and Mice1

NARUO KATSUTANI*, SHINJI YOSHITAKE{dagger}, HITOSHI TAKEUCHI{dagger}, JOHN C. KELLIHER{ddagger}, RONALD C. COUCH{ddagger},2 and HIROSHI SHIONOYA*

*Department of Drug Safety Research, Eisai Co., Ltd. Kawashima-cho, Hashima, Gifu 501-61, Japan {dagger}Tsukuba Research Laboratories, Eisai Co., Ltd. Takodai, Tsukuba-shi, Ibaraki 300-26, Japan {ddagger}Primate Research Institute, Holloman Air Force Base Alamogordo, New Mexico 88330-1027

Received November 4, 1991; accepted May 18, 1992

Immunogenic properties of second generation human tissue plasminogen activator (tPA) derivatives were examined in chimpanzee and mouse systems. Five species of modified tPAs (mtPAs) (designated 2660, 2663, 2810, 8000, and 9200), recombinant native tPA or bovine serum albumin (BSA) as a positive control were subcutaneously injected nine times at suitable intervals into chimpanzees, genetically the closest species to man. These animals were tested for antigen(Ag)-specific antibodies to the corresponding proteins by means of enzyme-linked immunosorbent assay and Western blot analysis. Neither 9200, one of the five mtPAs tested, nor tPA was immunogenic, although BSA and the other four mtPAs were immunogenic under these conditions. Thus, an antigenic deter minant was not exposed by the modification on 9200 and this modified tPA is expected not to be immunogenic in humans. In the mouse studies, mice were immunized with mtPAs. Serum sam-pies from these animals were tested for antibodies to the mtPAs which did not concomitantly recognize native tPA by immune ad sorption of the antibodies to tPA. The amount of such antibodies alter the elimination of native tPA-reactive antibodies was little or none when the serum samples from 9200 and from the other mtPAs, except 8000, were tested. Taking into consideration the results of the chimpanzee studies, it can be concluded that Ag-specific antibodies are dominantly produced to unchanged epitopes present in modified proteins in the mouse system, in which the native protein is immunogenic. These results suggest that the chimpanzee model should be useful to predict immunogenicity of second generation recombinant proteins in man, while the mouse system adopted by us, which determines the newly generated epitopes of the modified proteins, is not sufficient.


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