Preclinical safety testing of species-specific proteins produced with recombinant DNA-technqiues

Abstract

Preclinical toxicity studies in animals with species-specific recombinant DNA products have now been performed for several years. An interim statement on the significance of these animal tests and their ability to predict adverse effects in humans therefore appears indicated, with the aim of deducing future testing strategies. The experience accumulated so far shows that the animal models have failed to predict adverse effects subsequently observed in man. Immunogenicity of these proteins further restricted the usefulness of standard toxicity tests. There is also increasing evidence that animal tests on the toxic potential of impurities contained in the products are markedly inferior in sensitivity to analytical and quality control methods. Thus, modified testing programs are proposed to demonstrate safety rather than target organ toxicity using rodents and small non-rodent species and restricted dosing; furthermore the study duration should be limited by the detection of immunogenic responses.

Overview of the nonclinical quality and toxicology testing for recombinant biopharmaceuticals produced in mammalian cells

“…The desired pharmacologic effects were not being obtained in the usual animal species employed in small molecule toxicology studies, and to make matters more complicated, immunological responses including production of neutralizing antibodies to the foreign proteins were being mounted within the time frames of the usual toxicology study. It was also observed that the results of nonclinical testing of species-specific proteins in animal studies did not adequately predict adverse effects later observed in the patient population because of the use of pharmacologically nonrelevant animal species and/or the development of anti-drug antibodies (Teelmann et al, 1986). Therefore, it was apparent at the outset that nonclinical safety testing of biotechnologyderived pharmaceuticals was going to be conducted on a caseby-case basis, with selection of the tests required being driven by such factors as the nature of the production cell substrate (bacterial or mammalian cell type used), the type of product (monoclonal antibody, recombinant protein, cellular vaccine, etc.…”

“…One outstanding issue that became apparent early on was that many of the recombinant proteins were highly species-specific, and selection of the appropriate animal models for predicting efficacy and target organ toxicity was going to be problematic because of lack of pharmacologic activity of proteins among various animal species due to structural (e.g. amino acid sequence) differences (Teelmann et al, 1986). The desired pharmacologic effects were not being obtained in the usual animal species employed in small molecule toxicology studies, and to make matters more complicated, immunological responses including production of neutralizing antibodies to the foreign proteins were being mounted within the time frames of the usual toxicology study.…”

Thirty years of preclinical safety evaluation of biopharmaceuticals: did scientific progress lead to appropriate regulatory guidance?

“…When the first biopharmaceuticals entered the market, it was already clear that the value of animal experimentation in the preclinical safety evaluation of biopharmaceuticals was limited due to species specificity and immunogenicity [1,3,5,16]. At the same time, the European Union expressed its ambition to reduce animal experimentation in Directive 86/609/EEC.…”

“…At that time it was already known that the classical preclinical safety evaluation procedure applied to small molecule therapeutics (SMTs) would not predict adverse effects of biopharmaceuticals [1]. The checkbox approaches used in the classical procedure were considered not appropriate [2,3].…”

“…When the first biopharmaceuticals received market approval many experts concluded that biopharmaceuticals have different safety concerns than SMTs and so the classical preclinical safety evaluation procedure would not provide useful results concerning the safety of biopharmaceuticals [1,2,4,5]. Due to the novelty and different safety concerns, scientific progress was necessary to enable the design of a scientific and rational preclinical safety evaluation procedure for biopharmaceuticals [3,4].…”