An Investigation Of Safety Evaluation Methods Of Biotechnology-derived Drugs

Following the advances made in the field of biotechnology, many new kinds of biotechnology-derived drugs are being developed. However, only few guidelines for the safety evaluation of these new drugs are available, in China and internationally. As studies of these drugs progress a number of questions emerge, such as selecting sensitive animal species, dose levels to be used, duration of the administration period, which specific parameters should be evaluated etc.The purpose of this study was to select sensitive animal species and methods for investigating specific parameters which could provide an experimental basis for future Chinese guidelines of biotechnology-derived drugs.Repeat dose toxicity studies were performed to study the effects of the oncolytic adenoviruses H101 and H103. In these toxicity studies, guinea pigs and rhesus monkeys were chosen as experimental animals. At the end of the administration and recovery periods, major organs were collected from all animals. Both compounds were of low toxicity and the effects shown to be reversible. Furthermore, the preclinical results of H101 were in agreement with the adverse effects observed in clinical studies. Antibody detection in plasma samples was positive and time dependent for both compounds. H101 was distributed to cervical lymph nodes in guinea pigs as shown by PCR, while H103 did not show any tissue distribution by the PCR and RT-PCR techniques in rhesus monkeys.The present studies provide experimental data for toxicity evaluations of oncolytic adenoviruses and show that the guinea pig and rhesus monkey models can be used for safety evaluation of gene therapy involving virus carriers. Furthermore the guinea pig's immune system is more sensitive than that of primates.Toxicity studies of a biotechnology-derived vaccine, the recombinant human erbB3 fragment 483-540, were also performed. The erbB3 fragment 483-540 is a therapeutic cancer vaccine, aiming at the ErbB3 antigen and inducing a specific immunological response. It can be used to treat breast cancers highly expressing ErbB2. The FVB/N neu transgenic mice spontaneously develop breast cancer highly expressing ErbB2 and can thus be used as a model for pharmacodynamic studies of breast cancer therapies. The FVB/N neu transgenic mice and cynomolgus monkeys were chosen for long term toxicity studies. Effects of erbB3 on the immunological system were noted in the mice. Positiveand specific antibody reactions were observed in both species. Thus, transgenic mice and cynomolgus monkeys were shown to be useful experimental models for safety evaluation.Transgenic animals are expected to serve as models for safety evaluation of biotechnologically derived drugs in the future. Toxicity studies would benefit from the use of transgenic mice and monkeys since results would be more representative of those of clinical trials.Many biotechnology-derived drugs are based on human proteins and their effects on CYP450s have previously been ignored. Thus there are no guidelines regarding the toxicity effects of proteins on CYP450s. This thesis includes the study of the effects of rh-IL-11 on the hepatic CYP450s in rats. Rh-IL-11 is a multifunctional cytokine with hematopoietic and anti-inflammatory activities. It is mainly used to elevate the platelet count in cancer patients with chemotherapy-induced thrombocytopenia.No significant changes of the contents of microsomal proteins, the total CYP450s and the specific activity of CYP2E1 were observed after repeated rh-IL-11 administration for three months in rats. However, rh-IL-11 significantly decreased the specific activity of CYP2A2 in female rats and that of CYP1A1 in both male and female rats compared with the control group. Thus, the effects of the drug on the activities of CYP450s should be considered when it is co-administered with aromatic hydrocarbon drugs, such as cyclophosphamide, coumarin, testosterone and others. It should be emphasized that it is as important to evaluate the effects of biotechnology-derived drugs as of synthetic drugs on CYP450s to prevent second...