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Biopharmaceuticals, an Introductory Overview

1.1 Introduction to Pharmaceutical Products

Pharmaceutical substances form the backbone of modern medicinal therapy. Such drugs may be categorized in a number of ways, such as by intended therapeutic application (e.g. anticancer agents, anticoagulants, or anesthetics), by their chemical structure, by their mode of action, or by how they are synthesized.

Most traditional pharmaceuticals are low molecular mass, organic chemicals (Table 1.1). Although some (e.g. aspirin) were originally isolated from biological sources, most are now manufactured by direct chemical synthesis, for various economic and/or technical reasons. Two types of manufacturing company thus comprise the “traditional” pharmaceutical sector: the chemical synthesis facilities, which manufacture the raw chemical ingredients (“fine chemicals”) in bulk quantities; and the finished product pharmaceutical facilities, which purchase these raw bulk ingredients, formulate them into final pharmaceutical products, and supply these products to the market.

In addition to chemically synthesized drugs, a range of pharmaceutical substances are still obtained by direct extraction from biological material that produces these substances naturally. Such products, some major examples of which are listed in Table 1.2, may thus be described as products of traditional biotechnology. More recently, many pharmaceuticals produced in or by engineered biological systems have come to market, and these have been called “biopharmaceuticals.” The term “biopharmaceutical” was first used in the 1980s to describe therapeutic proteins produced by modern biotechnological techniques, specifically via genetic engineering (Chapter 5) or, in the case of monoclonal antibodies at that time, by hybridoma technology (Chapter 9).

Table 1.1 Some traditional pharmaceutical substances that are generally produced by direct chemical synthesis.

Table 1.2 Some pharmaceuticals that were traditionally obtained by direct extraction from biological source material. Many of the protein-based pharmaceuticals listed are now also produced by genetic engineering.

Although the majority of biopharmaceuticals now approved or in development are proteins (Box 1.1 and Chapter 4) produced via genetic engineering, this term now also encompasses nucleic-acid-based, i.e. deoxyribonucleic acid (DNA)- or ribonucleic acid (RNA)-based products, as well as engineered whole-cell-based products (Chapter 16).

Box 1.1 Overview of protein structure

Proteins are large molecules made up of one or more chains of amino acids, known as polypeptides. These amino acids are linked by peptide bonds, and the sequence of these amino acids is determined by the gene encoding the polypeptide. Once synthesized, the polypeptide chain folds into a unique three-dimensional shape, which is crucial for its biological function. This specific shape is stabilized by various weak interactions, such as hydrogen bonds, and is dependent on the amino acid sequence. Any changes in the sequence can alter the shape and, consequently, the function of the protein.

Protein structure can be described at four levels:

• Primary structure: The specific sequence of amino acids in the polypeptide chain, including the positioning of any disulfide bonds.
• Secondary structure: Regular patterns formed by adjacent amino acids, such as alpha-helices and beta-strands, often over short sequences.
• Tertiary structure: The overall three-dimensional arrangement of all atoms in the polypeptide, including regions of secondary structure and less ordered areas like loops.
• Quaternary structure: The overall spatial arrangement of multiple polypeptide subunits in a protein composed of more than one polypeptide chain.

Most proteins from eukaryotes undergo covalent modifications during or after their synthesis on ribosomes. These modifications, known as co-translational and post-translational modifications (PTMs), include processes like glycosylation, where sugar chains are attached to specific points on the polypeptide backbone.

Amino acid sequence of human interleukin 22 (IL-22; 179 amino acids, each represented by its single letter designation), and its associated 3-dimensional structure (conformation). Data courtesy of the NCBI (www.ncbi.org); Sequence information: GenBank, AAH69308.1. Structural information: Protein Data Bank (PDB) ID 1M4R.

Terms such as “biologic,” “biopharmaceutical” and “products of pharmaceutical biotechnology,” or “biotechnology medicines” have now become an accepted part of the pharmaceutical lexicon. These terms are sometimes used interchangeably but can mean different things to different people.

A summary of their meaning, as used in this book, is provided in Table 1.3. In reality, such designations can be somewhat artificial. For example, insulin products extracted directly from the pancreas of slaughtered pigs would be considered as products of traditional biotechnology, whereas insulin products produced via genetic engineering would be considered as biopharmaceuticals. In addition, a small number of RNA-based products (siRNA and antisense products – Chapter 16) are often described as biopharmaceuticals, even though they are manufactured by direct chemical synthesis.

The pace of new drug discovery has grown significantly over the past half-century in particular. Biomedical research continues to broaden our understanding of the molecular mechanisms underlining both health and disease, facilitating a knowledge-based approach to drug identification and discovery. Disciplines such as genomics, proteomics, and bioinformatics help identify both new potential drugs, and in particular new potential drug targets (Chapter 2). Advances in analytical (bio)chemistry have led to the development of a range of technologies and instruments (for example, mass spectrometry) capable of detecting, quantifying, and elucidating the structure of biomolecules associated with health and disease. Some such advances have facilitated the rapid analysis of multiple samples (high-throughput screening), speeding up the screening and identification of both new drugs and/or drug targets very significantly. A potent example of how such scientific and technological advances can lead to rapid drug development was most recently provided by the COVID-19 pandemic, with the development of several effective vaccines and therapies within months of causative agent identification (Box 1.2).

Table 1.3 The meaning of the various indicated terms, as used in this book.