Of Biotechnology Derived Therapeutic Drugs

Barbara J. Mounho, Jeanine L. Bussiere, and Andrea B. Weir

CONTENTS

6.1 Introduction 134

6.2 Regulatory Overview of Biological Therapeutic Products 136

6.2.1 ICH S6: Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals 139

6.2.2 Relevant Animal Model 140

6.2.3 Nature of the Test Material 142

6.2.4 FDA Compliance 142

6.3 Types of Studies Considered Appropriate for Biologicals 142

6.3.1 Safety Pharmacology Studies 143

6.3.2 Exposure Assessment 143

6.3.3 Single-Dose Toxicity Studies 144

6.3.4 Repeated-Dose Toxicity Studies 144

6.3.5 Immunotoxicity Studies 144

6.3.6 Reproductive Performance and Developmental Toxicity Studies 146

6.3.7 Genotoxicity Studies 146

6.3.8 Carcinogenicity Studies 146

6.3.9 Local Tolerance Studies 147

6.3.10 Tissue Cross-Reactivity Studies for Monoclonal Antibodies 147

6.4 Use of Nonhuman Primates for Safety Testing 148

6.4.1 Immunotoxicity Testing in Nonhuman Primates 150

6.4.2 Reproductive Testing in Nonhuman Primates 152

6.5 Immunogenicity of Biological Products 154

6.6 Alternative Approaches Employed for the Safety

Assessment of Biologicals 158

6.7 Summary 160

References 161

6.1 INTRODUCTION

The emergence of and continuous advancement in recombinant DNA (rDNA), hybridoma, and cell culture technologies has led to an escalating production over the past 20 years of biotechnology-derived therapeutics (therapeutic proteins or bio-logicals) for use in various clinical indications. Biologicals are protein pharmaceuticals derived from living organisms and are distinguished from conventional (small molecule) pharmaceuticals by their manufacturing processes (biological sources vs. chemical/synthetic processes). Thus, the definition of biologicals encompasses protein therapeutics such as recombinant human proteins (i.e., cytokines and replacement enzymes) and monoclonal antibodies.1 Although vaccines and cell and gene therapy products can also fall under the definition of biologicals, these products have distinctive properties that distinguish them from biotechnology-derived therapeutics, and they will not be discussed in this chapter.

Recombinant protein therapeutics (biologicals) are produced from the genetic modification (rDNA techniques) of various expression systems such as mammalian cells [e.g., Chinese hamster ovarian (CHO) cells], bacteria (e.g., Escherichia coli), yeast, insects, or plants.2,3 Monoclonal antibody therapeutics initially were derived from hybridoma technology (fusing an immortalized cell and an antibody-producing cell) developed in the mid-1970s.4,5 Over the years, vast advances in antibody technology, such as the Xenomouse® (Abgenix, Inc., Fremont, CA), have resulted in the generation of fully human antibodies.5,6 The majority of biological drug products developed for therapeutic use are complex, large-molecular-weight molecules (>1000 Daltons), and include a diverse range of polypeptide or protein products, including recombinant human proteins such as cytokines, hormones, and growth factors, as well as fusion proteins (peptide fused to human IgG Fc) and monoclonal antibodies.7 The introduction of biological drug products has revolutionized the prevention and treatment of human disease by means of mimicking/supplementing a human endogenous protein (e.g., therapeutic biologicals such as growth hormone or erythropoietin), or by activating (agonistic) or blocking (antagonistic) a signaling pathway through specific receptor or ligand binding.

Biological therapeutic products were initially developed in the early 1980s. Before rDNA technology, the only source of biological drugs was animal or human tissues or serum (e.g., insulin). The first recombinant protein therapeutic was human insulin (produced in genetically modified bacteria), which was approved by the U.S. Food and Drug Administration (FDA) in 1982 for the treatment of diabetes.8,9 Several other biologicals generated by rDNA techniques have since been approved, including interferons [interferon-alpha-2b (Intron A®; Schering Corp., Kenilworth, NJ), first approved in 1986 for the treatment of hairy cell leukemia]; enzymes [recombinant tissue plasminogen activator (Alteplase®; Genentech, Inc., South San Francisco, CA), approved in 1987 for the treatment of acute myocardial infarction]; and growth factors [epoietin alfa (Epogen®; Amgen, Inc., Thousand Oaks, CA), approved in 1989 for the treatment of anemia associated with chronic renal failure].9-11

Monoclonal antibodies are immunoglobulin (IgG) molecules engineered to bind to specific antigens or epitopes on cells or tissues. Thus, the therapeutic advantage of monoclonal antibodies is their specificity to a particular epitope, which provides them with a highly targeted and selective therapeutic action.12 The first therapeutic monoclonal antibodies generated using hybridoma technology were murine-derived. Immunogenicity (an immune response to the therapeutic), however, is a major limitation of murine antibodies because the human immune system recognizes the murine antibody as foreign, and patients often produce human anti-mouse antibodies (HAMA) against the drug.13,14 Consequently, the development of HAMA limited the chronic administration of murine antibodies (immunogenicity will be described in further detail later in this chapter). Over time, a variety of sophisticated techniques have been developed to overcome the problem of HAMA by replacing the murine regions of an antibody with human components. As illustrated in Figure 6.1, chimeric antibodies, consisting of approximately 34% murine and approximately 66% human components, are generated by joining the antigen binding region of a murine antibody to human IgG constant domains; "humanized" antibodies (5% to 10% murine and 90% to 95% human) are produced by implanting the antigen recognition domain from the murine IgG into the human IgG framework.5,7,15 The innovative development of Xenomouse® technology (mice genetically engineered to express human IgGs but lacking functional murine IgGs) has now made the generation of fully human monoclonal antibodies possible.5,6,14

The first approved therapeutic antibody was muromonab-CD3 (Orthoclone OKT-3®; Ortho Biotech Products, L.P., Bridgewater, NJ), a murine monoclonal antibody (IgG2a) that recognizes the cluster of differentiation-3 (CD3) receptor complex on human T lymphocytes; OKT-3 was approved for the prevention of allograft rejection in renal transplantation in 1986.9,16 It took several more years before the next therapeutic antibody was approved. Abciximab (ReoPro®; Centocor, Inc., Malvern, PA and Eli Lilly, Indianapolis, IN) was approved in 1994 for the treatment of blood clot complications in patients undergoing cardiac procedures.5 Shortly thereafter, numerous antibodies were approved for various clinical indications such as rituximab (Rituxan®; Genentech, Inc., South San Francisco, CA and Biogen Idec, Inc., Cambridge, MA), approved for the treatment of non-Hodgkin's lymphoma in 1997; infliximab (Remicade®; Centocor, Inc., Malvern, PA), approved in 1998 for rheumatoid arthritis; and bevacizumab (Avastin®; Genentech, Inc., South San Francisco, CA), which was approved in 2004 for the treatment of colorectal cancer.12,17

The key purpose of nonclinical toxicology studies for any pharmaceutical product is to provide adequate safety data to move a drug candidate forward into

Murine Chimeric Humanized Fully Human

100% Murine 34% Murine 5-10% Murine 100% Human H Murine H Human

FIGURE 6.1 Advancement of monoclonal antibody technology.

human clinical trials. Primary objectives of toxicology studies in animals include: (1) identify potential adverse clinical effects and target organs of toxicity; (2) characterize potential underlying mechanisms of toxicity; (3) establish a safe starting dose in humans; (4) determine potential parameters that can be monitored in clinical trials; and (5) provide the necessary data to support labeling claims.18 Because of their complex structural and biological nature, most biological products have unique properties that can create various challenges in conducting nonclinical safety assessment studies for these molecules.

Conventional toxicity testing applied to small-molecule pharmaceuticals is often not appropriate for biologicals.19 For example, most biological therapeutic products are human proteins that are highly targeted to a human receptor or are antibodies specific for a human protein or receptor and, thus, conducting safety studies in animal species commonly used in toxicology studies, such as rodents and dogs, would not be relevant for biologicals. Because of the species-specific nature of biologicals, toxicology studies must be conducted in a pharmacologically relevant animal species, and for many biologicals, the nonhuman primate is the only relevant animal model. Conducting safety evaluation studies in nonhuman primates can have numerous challenges and limitations that are discussed in detail later in this chapter.

Before being marketed in the United States and other countries, all pharmaceuticals, including biological products, are required to undergo a comprehensive safety evaluation and regulatory review. Although the regulatory review processes applied to biologicals are the same as those applied to small-molecule pharmaceuticals, regulatory guidelines specific to issues and challenges associated with the unique properties of biologicals have been generated to harmonize the nonclinical and clinical testing required for the development and worldwide approval of these molecules.

The complex nature of biological drug products gives rise to their distinctive properties, making these molecules fundamentally different from traditional (small-molecule) pharmaceuticals. Because biologicals have diverse characteristics, critical points such as selection of a relevant animal species and the immunogenic potential of the drug must be considered in the design and interpretation of nonclinical safety studies for these molecules. Additionally, since each biological product has its own distinct properties, each one should be considered individually, and a science-based, case-by-case approach should be applied to develop nonclinical safety programs for biologicals.2021

The concepts that will be reviewed in this chapter include: (1) the regulatory procedures and guidelines that apply to biologicals; (2) the types of toxicology studies that are applicable to biological products; (3) limitations of animal models used in the safety assessment of biological products; (4) scientific challenges that can arise due to the unique properties of these protein molecules; and (5) potential alternative models that can be utilized for the nonclinical safety evaluation of these molecules.

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