The age of biopharmaceuticals

Biomedical research continues to broaden our understanding of the molecular mechanisms underlining both health and disease. Research undertaken since the 1950s has pinpointed a host of proteins produced naturally in the body that have obvious therapeutic applications. Examples include the interferons and interleukins (which regulate the immune response), growth factors, such as erythropoietin (EPO; which stimulates red blood cell production), and neurotrophic factors (which regulate the development and maintenance of neural tissue).

h2n nh2

NH2 Prontosil rubrum

Sulphanilamide

COOH

PABA

OH H

OH H

COOH

Pteridine derivative

PABA

Glutamic acid

Tetrahydrofolic acid (d)

Figure 1.1 Sulfa drugs and their mode of action. The first sulfa drug to be used medically was the red dye prontosil rubrum (a). In the early 1930s, experiments illustrated that the administration of this dye to mice infected with haemolytic streptococci prevented the death of the mice. This drug, although effective in vivo, was devoid of in vitro antibacterial activity. It was first used clinically in 1935 under the name Streptozon. It was subsequently shown that prontosil rubrum was enzymatically reduced by the liver, forming sulfanilamide, the actual active antimicrobial agent (b). Sulfanilamide induces its effect by acting as an anti-metabolite with respect to poro-aminobenzoic acid (PABA) (c). PABA is an essential component of tetrahydrofolic acid (THF) (d). THF serves as an essential cofactor for several cellular enzymes. Sulfanilamide (at sufficiently high concentrations) inhibits manufacture of THF by competing with PABA. This effectively inhibits essential THF-dependent enzyme reactions within the cell. Unlike humans, who can derive folates from their diets, most bacteria must synthesize it de novo, as they cannot absorb it intact from their surroundings

Although the pharmaceutical potential of these regulatory molecules was generally appreciated, their widespread medical application was in most cases rendered impractical due to the tiny quantities in which they were naturally produced. The advent of recombinant DNA technology (genetic engineering) and monoclonal antibody technology (hybridoma technology) overcame many such difficulties, and marked the beginning of a new era of the pharmaceutical sciences.

Recombinant DNA technology has had a fourfold positive impact upon the production of pharmaceutically important proteins:

• It overcomes the problem of source availability. Many proteins of therapeutic potential are produced naturally in the body in minute quantities. Examples include interferons (Chapter 8), interleukins (Chapter 9) and colony-stimulating factors (CSFs; Chapter 10). This rendered impractical their direct extraction from native source material in quantities sufficient to meet likely clinical demand. Recombinant production (Chapters 3 and 5) allows the manufacture of any protein in whatever quantity it is required.

• It overcomes problems of product safety. Direct extraction of product from some native biological sources has, in the past, led to the unwitting transmission of disease. Examples i nclude the transmission of blood-borne pathogens such as hepatitis B and C and human immunodeficiency virus (HIV) via infected blood products and the transmission of Creutzfeldt-Jakob disease to persons receiving human growth hormone (GH) preparations derived from human pituitaries.

• It provides an alternative to direct extraction from inappropriate/dangerous source material. A number of therapeutic proteins have traditionally been extracted from human urine. Follicle-stimulating hormone (FSH), the fertility hormone, for example, is obtained from the urine of post-menopausal women, and a related hormone, human chorionic gonadotrophin (hCG), is extracted from the urine of pregnant women (Chapter 11). Urine is not considered a particularly desirable source of pharmaceutical products. Although several products obtained from this source remain on the market, recombinant forms have now also been approved. Other potential biopharmaceuticals are produced naturally in downright dangerous sources. Ancrod, for example, is a protein displaying anti-coagulant activity (Chapter 12) and, hence, is of potential clinical use. It is, however, produced naturally by the Malaysian pit viper. Although retrieval by milking snake venom is possible, and indeed may be quite an exciting procedure, recombinant production in less dangerous organisms, such as Escherichia coli or Saccharomycese cerevisiae, would be considered preferable by most.

• It facilitates the generation of engineered therapeutic proteins displaying some clinical advantage over the native protein product. Techniques such as site-directed mutagenesis facilitate the logical introduction of predefined changes in a protein's amino acid sequence. Such changes can be as minimal as the insertion, deletion or alteration of a single amino acid residue, or can be more substantial (e.g. the alteration/deletion of an entire domain, or the generation of a novel hybrid protein). Such changes can be made for a number of reasons, and several engineered products have now gained marketing approval. An overview summary of some engineered product types now on the market is provided in Table 1.3. These and other examples will be discussed in subsequent chapters.

Despite the undoubted advantages of recombinant production, it remains the case that many protein-based products extracted directly from native source material remain on the market. In certain circumstances, direct extraction of native source material can prove equally/more attractive than recombinant production. This may be for an economic reason if, for example, the protein is produced in very large quantities by the native source and is easy to extract/purify, e.g. human serum albumin (HSA; Chapter 12). Also, some blood factor preparations purified from donor blood actually contain several different blood factors and, hence, can be used to treat several haemophilia patient types. Recombinant blood factor preparations, on the other hand, contain but a single blood factor and, hence, can be used to treat only one haemophilia type (Chapter 12).

The advent of genetic engineering and monoclonal antibody technology underpinned the establishment of literally hundreds of start-up biopharmaceutical (biotechnology) companies in

Table 1.3 Selected engineered biopharmaceutical types/products that have now gained marketing approval. These and additional such products will be discussed in detail in subsequent chapters

Product description/type

Faster acting insulins (Chapter 11) Slow acting insulins (Chapter 11) Modified tissue plasminogen activator (tPA; Chapter 12)

Modified blood factor VIII

(Chapter 12) Chimaeric/humanized antibodies (Chapter 13)

'Ontak', a fusion protein (Chapter 9)

Alteration introduced

Modified amino acid sequence Modified amino acid sequence Removal of three of the five native domains of tPA

Deletion of 1 domain of native factor VIII Replacement of most/virtually all of the murine amino acid sequences with sequences found in human antibodies Fusion protein consisting of the diphtheria toxin linked to interleukin-2 (IL-2)

Rationale

Generation of faster acting insulin Generation of slow acting insulin Generation of a faster acting thrombolytic (clot degrading) agent

Production of a lower molecular mass product Greatly reduced/eliminated immunogenicity. Ability to activate human effector functions Targets toxin selectively to cells expressing an IL-2 receptor the late 1970s and early 1980s. The bulk of these companies were founded in the USA, with smaller numbers of start-ups emanating from Europe and other world regions.

Many of these fledgling companies were founded by academics/technical experts who sought to take commercial advantage of developments in the biotechnological arena. These companies were largely financed by speculative monies attracted by the hype associated with the establishment of the modern biotech era. Although most of these early companies displayed significant technical expertise, the vast majority lacked experience in the practicalities of the drug development process (Chapter 4). Most of the well-established large pharmaceutical companies, on the other hand, were slow to invest heavily in biotech research and development. However, as the actual and potential therapeutic significance of biopharmaceuticals became evident, many of these companies did diversify into this area. Most either purchased small, established biopharmaceutical concerns or formed strategic alliances with them. An example was the long-term alliance formed by Genentech (see later) and the well-

Table 1.4 Pharmaceutical companies who manufacture and/or market biopharmaceutical products approved for general medical use in the USA and EU

Sanofi-Aventis

Hoechst AG

Bayer

Wyeth

Novo Nordisk

Genzyme

Isis Pharmaceuticals

Abbott

Genentech

Roche

Centocor

Novartis

Boehringer Manheim

Serono

Galenus Manheim

Organon

Eli Lilly

Amgen

Ortho Biotech

GlaxoSmithKline

Schering Plough

Cytogen

Hoffman-la-Roche

Immunomedics

Chiron

Biogen

established pharmaceutical company Eli Lilly. Genentech developed recombinant human insulin, which was then marketed by Eli Lilly under the trade name Humulin. The merger of biotech capability with pharmaceutical experience helped accelerate development of the biopharmaceutical sector.

Many of the earlier biopharmaceutical companies no longer exist. The overall level of speculative finance available was not sufficient to sustain them all long term (it can take 6-10 years and US$800 million to develop a single drug; Chapter 4). Furthermore, the promise and hype of biotechnology sometimes exceeded its ability actually to deliver a final product. Some biopharmaceutical substances showed little efficacy in treating their target condition, and/or exhibited unacceptable side effects. Mergers and acquisitions also led to the disappearance of several biopharmaceutical concerns. Table 1.4 lists many of the major pharmaceutical concerns which now manufacture/market biopharmaceuticals approved for general medical use. Box 1.1 provides a profile of three well-established dedicated biopharmaceutical companies.

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