Peptides, mAbs, bispecifics, oh my! clinical pharmacology challenges in the development of biologics.

Abstract

Biotechnology, defined as the use of living organisms to make useful products, is an ancient tool in the treatment of disease and improvement in health. There are the obvious examples of animal husbandry to improve livestock yield and crop manipulation to select preferred food sources and thus improving health through better nutrition. Inoculation was likely practiced in Africa, India, and China long before the 18th century when travelers from Istanbul to Western Europe, first described the process of intradermal injection of material from pustules of smallpox victims to nonimmune persons with the goal of preventing infection.1 Early applications of biotherapeutics were, by necessity, largely empiric as there were only limited methods of understanding genetics or immunology. When evidence of missing proteins was described, there was an attempt to replace them with similar material from animals or humans. Banting and Macleod, building on the work of others, described the cause of diabetes a deficiency of a substance produced by the islets of Langerhans, insulin. Only 7 months later, the first administration of insulin to a boy with diabetes occurred.2 Unfortunately, missing substances were not easily replaced, but work to understand the mechanisms of therapeutic misadventures of incompatible or contaminated blood administration, for example, has led to discovery and later quantification of the immunology of blood typing as well as understanding of the issues of contamination with various viruses. More than 30 years ago, a new era was announced in pharmaceutical drug development: a brave new world of biotechnology. New methods were available to harness the synthetic ability of yeast and other cells to manufacture proteins that were either identical to human proteins, such as insulin, or were entirely new constructs, directed at targets such as the CD3 antigen located on mature T-cells.3 Exciting discoveries occurred with increasing frequency as targets were described, antibodies and ligands and other platforms were synthesized, and clinical trials initiated. A recent search of the term “monoclonal antibody” yielded over 3,000 clinical trials listed on the Clinicaltrials.gov website. There are now hundreds of commercially available biotherapeutic agents with dozens of different indications. As biotechnology products enter the mature phase of their life cycle with biosimilar products entering the market, it is a good time to pause and reflect on how clinical pharmacology understanding and methods, largely applied previously to small molecules, have been used in the discovery, development, and utilization of the many biologics that are important additions to modern medicine. Much of what was known about clinical pharmacology had to be adapted to these new medicines. How were the structures of new drugs described? How did the structures change with different manufacturing methods? Why did seemingly modest changes in manufacturing processes sometimes result in large changes in protein structure or immunogenicity? What was the relationship between structure and clinical response? What was the appropriate preclinical animal model to use if a chimeric or humanized protein caused antidrug antibody formation? What was an appropriate quantitative standard to use to ascribe potency? What were appropriate bioanalytical conditions? Clinical pharmacology is the science of describing and understanding mechanisms of action, pharmacokinetics, concentration-effect relationships, and therapeutics within the context of drug development and clinical medicine. Things became more exciting with methods to clone receptors and breed animals without receptors (knock-out). Antibody engineering technology allowed specific monoclonal antibodies directed toward a specific receptor with more precision than small molecules allowed. Everything in biotherapeutic research and development seemed difficult. The production of biotherapeutics was long, required specialized equipment and facilities. Results from preclinical models to allow for straightforward assessment of toxicology were difficult to interpret because humanized therapeutic proteins could cause immune response in the species used in toxicology, greatly reducing systemic exposure and making calculation of exposure ratios impossible. Bioanalytical techniques also needed to be revised. However, we have persevered and strategies and methods have been developed and now clinical pharmacologists are frequently “bilingual” familiar with small molecules as well as the conventions and methods of biotechnology products. The collection of papers in this supplement of the Journal takes a fresh look at each of these areas of clinical pharmacology from the perspective of biologics. While some are review papers, others present specific examples of more general principles. As we read them, we see that biotechnology need not be set aside as a separate body of knowledge, but is more appropriately an extension of what we learn as we learn clinical pharmacology. For each disease, we can include the biotherapeutic option along with other modalities. Although biotherapeutic agents have some common properties, such as potential for developing immunological response and poor oral bioavailability, they also differ from each other in pharmacokinetics, pharmacodynamics, and clinical activity. Although clinicians have perhaps not treated biotherapeutics differently than small molecules, drug development proceeded along very different lines. Initially, a different part of the FDA reviewed biologic licensing applications than reviewed new drug applications. Happily, there was recognition that collaboration was needed across the 2 divisions and joint guidelines were developed so that the clinical pharmacology portions of drug development could be reasonably applied to most drug molecules irrespective of whether they were small or “large” molecules as biotherapeutics are sometimes referred to. Most applications are now reviewed by the same division. The papers in this supplement are organized along the lines of drug development. Development of a new therapeutic agent, whether conventional or biologic, begins with a description of its chemical class, pharmaceutical characteristics, and hypothesis about how it causes its pharmacological action. The paper by Aldeghaither et al4 provides an overview of the many classes of biotherapeutics beyond peptides and monoclonal antibodies. Rathi and Meibohm5 complement the overview with a more focused discussion of bispecific antibody constructs. After the benchtop assessment of the structure and structure-activity relationships, understanding of the pharmacokinetics of a new medication is a first step to being able to quantify the exposure response and arrive at the best dose to use in the treatment of patients. Glassman et al6 provide a comprehensive review of distribution and assessment of protein binding of monoclonal antibodies, nicely describing key characteristics of this important class of biologics. In the absence of the development of antidrug antibodies, description of pharmacokinetic parameters proceeds in a similar manner for biotherapeutics as it does for small molecules. However, biotherapeutics are proteins and immunological response is part of the charm of these agents and so immunogenicity, pharmacokinetics, and clinical response are intimately entwined. Three of the papers in this supplement involve some aspect of this. Vande Casteele and Gils7 present the idea that because the systemic exposure (area under the curve or steady-state concentration) of anti-TNF monoclonal antibodies has been shown to be predictive of clinical response, therapeutic drug monitoring is warranted. Mould and Dubinsky8 then describe how the information contained in TDM can be harnessed to better manage patients taking these agents through the use of dashboard systems. Finally, Xu and Zhou9 explain how concomitant medications that suppress/modify immunological responses to biotherapeutics can preserve the good responses that would otherwise not be achieved or would be lost through development of antibodies to the biotherapeutic agent. Pharmacodynamics is also important to assessing the right dose. Sometimes clinical endpoints may not be easily measurable in early stage of biotherapeutic development and drug concentrations cannot be measured at the site of action. Zheng et al10 examine the utility of target measurements as biomarkers of target engagement and clinical efficacy. Two papers offer overviews of drug development of biotherapeutics. Perza Ruixo et al11 describe denosumab which is used to control bone metastases in patients with solid tumors. Alemayehu et al12 provide an update of vaccines explaining how things have changed in vaccine development since Jenner's first experiments and offer a peek at potential noninfectious examples of vaccines. Important to clinical pharmacology are the expansion packs to basic drug development: new patient groups, new indications, new markets, and life cycle management. As we all recognize, drug development is so expensive in both time and resources that no effort should be wasted. Zhang and coauthors13 describe the development of biologics in pediatric patients. Much of what they advocate is true for small molecules as well. A product is more likely to pay its way and have a more secure supply chain if the indication is consistent globally and similar doses and dosage forms can be used around the world. Damle et al14 describe considerations for biologics in emerging markets. Part of the life cycle of impactful therapeutic agents is the development of biosimilar products. Scott et al15 describe a Canadian regulatory perspective on this newly emerging subject. So, more than 90 years after the isolation of insulin, 30 years after the approval of the first monoclonal antibody, and 10 years after the mapping of the human genome, it is good to read this collection of papers to consolidate our understanding of clinical pharmacology principles within the context of biotherapeutics and to get ready for the future!