Genotoxicity testing of biotechnology-derived products - Report of a GUM task force

Various aspects of genotoxicity testing of biotechnology-derived products a re discussed based on information gathered from a questionnaire which was s ent to about 30 predominantly European companies. Feedback was received fro m 13 companies on 78 compounds, mostly recombinant proteins but also on a n umber of nonrecombinant proteins, which had been assessed for genotoxicity in a total of 177 tests. Four of the 78 compounds appeared to elicit reprod ucible genotoxic effects. For one of these compounds, the activity could be related to a nonpeptidic linker molecule. No scientifically convincing rat ionale for the other three compounds could be established, although, at lea st for two compounds, their activity may be connected with the enzymatic/ho rmonal activity. In addition to the survey, published reports on genotoxici ty testing of biotechnology products were reviewed. The data are discussed relative to whether genotoxicity testing is a valuable exercise when assess ing potentially toxic liabilities of biotechnology-derived compounds. It is concluded that genotoxicity testing is generally inappropriate and unneces sary, a position which is in accordance with the available guidelines addre ssing this area. For the 'average' protein, electrophilic reactions are dif ficult to envision. Indirect reactions via DNA metabolism and growth regula tion seem possible for only very specific proteins such as nucleases, growt h factors, cytokines. No information on testing of different types of biote chnology-derived products (e.g., ribozymes, antisense-oligonucleotides, DNA vaccines) has been received in the questionnaires. Discussion of their pot ential to cause genotoxic changes was based on literature reports. Even for those products for which concerns of genotoxic/tumourigenic potential cann ot be completely ruled out, e.g., because of their interaction with DNA met abolism or proliferation control, the performance of standard genotoxicity assays generally appears to be of little value. All information, including also information on the occurrence of genotoxic impurities, has been utiliz ed to formulate a decision tree approach for the genotoxicity testing of bi otechnology-derived products. (C) 1999 Elsevier Science B.V. All rights res erved.