The role of the toxicologic pathologist in the preclinical safety evaluation of biotechnology-derived pharmaceuticals

Biotechnology-derived pharmaceuticals, or biopharmaceuticals, represent a s pecial class of complex, high-molecular weight products, such as monoclonal antibodies, recombinant proteins, and nucleic acids. With these compounds, it is not appropriate to follow conventional safety testing programs, and the preclinical "package" for each biopharmaceutical needs to be individual ly designed. In addition to standard histopathology, the use of molecular p athology techniques is often required either in conventional animal studies or in in vitro tests. In this review, the safety evaluation of biopharmace uticals is discussed from the perspective of the toxicologic pathologist an d appropriate examples are given of the use of molecular pathology procedur es. Examples include the use of in situ hybridization to localize gene ther apy vectors, the assessment of vector integration into genomic DNA by the p olymerase chain reaction (PCR), and the use of immunohistochemistry to eval uate the potential cross-reactivity of monoclonal antibodies. In situ PCR t echniques may allow for confirmation of the germ cell localization of nucle ic acids and may therefore facilitate the risk assessment of germline trans mission. Increased involvement with biopharmaceuticals will present challen ging opportunities for the toxicologic pathologist and will allow for much greater use of molecular techniques, which have a critical role in the prec linical development of these compounds.