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Carcinogenicity of Biopharmaceuticals

  • Chapter
Genotoxicity and Carcinogenicity Testing of Pharmaceuticals

Abstract

The physicochemical and biological properties of biopharmaceuticals are, in many aspects, different from small molecule drugs. These differences must also be taken into account when evaluating the risk of carcinogenicity in humans. For example, because of their expected biological activity, growth factors or immunomodulators present an inherent risk for potentially enhancing tumor incidence in humans.

The present chapter reviews the background for this position of biotechnologically-derived pharmaceuticals. Growth factors can be seen as oncogenes, as these proteins will stimulate cell surface receptors related to cell proliferation. In this respect, ICH S6(R1) deviates from the common approach for carcinogenicity testing, as generally 2-year bioassay studies are not expected for these products. Also, for immunomodulators, the regulatory guidance acknowledges an inherent risk for cancer when immunosuppressive activity can be expected based on the pharmacology of the compound (e.g., impaired immune surveillance).

In this chapter, a few case studies are presented, illustrating different approaches in evaluating the carcinogenic potential of biopharmaceuticals. Furthermore, approaches to the translation of these findings to the human situation are discussed. Insulin-like growth factor and insulin are different in mitogenic and metabolic activity by stimulation of IGF1- and Insulin receptor A or B, respectively. Insulin analogues such as Insulin AspB10 and insulin glargine have been analyzed in this respect by novel in vitro and in vivo strategies, and this approach reveals its usefulness from a regulatory point of view.

GLP1-agonists induce thyroid C-cell tumors by a direct action at the C-cell, and we have described a pharmacodynamic/pharmacokinetic approach to model the relationship between exposure and the induction of thyroid hyperplasia or adenoma (dependent on the compound).

By virtue of their pharmacology, some monoclonal antibodies are also known to be associated with occurrence of tumors in humans, and an overview of these reported cases is also included in this chapter. The concerns of an increased cancer risk associated with medicines may arise at any time during a drug’s life cycle: in early phases during development, or after many years of use in clinical practice. Pharmacovigilance represents the science and activities related to the detection, assessment, understanding and prevention of adverse effects or other drug-related problems. In this section, we review a series of medicines for which cancer has been a suspected or actual risk detected, as well as the problems that are encountered in studying and communicating such cancer risks or the uncertainties about these risks.

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Authors and Affiliations

  1. Safety Assessment, GlaxoSmithKline, LLC., Philadelphia, PA, USA

    Maggie Dempster

  2. Section on Pharmacological, Toxicological and Biotechnological Assessment, Medicines Evaluation Board, Utrecht, The Netherlands

    Kris Siezen & Jan Willem van der Laan

  3. Division of Toxicology, Leiden Academic Center for Drug Research, Leiden, The Netherlands

    Bas ter Braak & Jan Willem van der Laan

  4. Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands

    Willem van den Brink, Annette Emerenciana & Francesco Bellanti

  5. Section on Pharmacovigilance, Medicines Evaluation Board, Utrecht, The Netherlands

    Ruben G. Duijnhoven & Marcel Kwa

  6. Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    Ruben G. Duijnhoven

  7. Center for Health Protection, National Institute for Public Health and the Environment, Bilthoven, The Netherlands

    Jan Willem van der Laan

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    Michael J. Graziano

  2. ToxRox Consulting, McLean VA 22101, Virginia, USA

    David Jacobson-Kram

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Dempster, M. et al. (2015). Carcinogenicity of Biopharmaceuticals. In: Graziano, M., Jacobson-Kram, D. (eds) Genotoxicity and Carcinogenicity Testing of Pharmaceuticals. Springer, Cham. https://doi.org/10.1007/978-3-319-22084-0_8

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