Introduction To Biopharmaceuticals

1.1. BIOTECHNOLOGY VERSUS PHARMACEUTICAL BIOTECHNOLOGY

1.2. HISTORICAL PERSPECTIVE OF PHARMACEUTICAL BIOTECHNOLOGY

1.3. NOT ALL PROTEIN DRUGS AND VACCINES OF THE SAME NAME ARE IDENTICAL

Since the discovery in 1800 that the human body is composed of cells and proteins that are susceptible to but can also fight off pathogenic microbes, the perceived battlefield has challenged our imagination to develop biopharmaceuticals—biologically based therapeutic products. While biotechnology today is seen as the cutting edge of biological sciences, the use of biological entities as therapeutic agents has been extant since the early 1800s.

The considerable history of biopharma-ceuticals notwithstanding, the refinement of our abilities to produce recombinant macro-

molecules and monoclonal antibodies is a recent achievement and, as depicted in Figure 1.1, is the result of an exponential growth in the knowledge of biological processes and engineering advancements. Protein-and antibody-based therapies that require milligrams of materials for pharmaceutical use cannot be consistently, safely, and cost-effectively applied without these recent biotechnology milestones that include the basic principles of recombinant DNA and cell and fermentation technologies.

Today biotechnology-based pharmaceutical companies, while still relatively small,

Biotechnology and Biopharmaceuticals, by Rodney J. Y. Ho and Milo Gibaldi ISBN 0-471-20690-3 Copyright © 2003 by John Wiley & Sons, Inc.

DNA = double helix DNA polymerase Cell culture

protein

100 - /Mendel's genetic

1 900 1 940

Human genome map Identification of disease genes Animal cloning Human gene therapy IND Transgenic mouse PCR technique Recombinant insulin

Yeast expression vector-fermentation J human genes expressed in E. coli DNA sequencing technique Monoclonal antibody technology Genetic engineering-rDNA technology Restriction endonucelase Synthesis of gene in vitro Genetic code

■ In vitro enzyme synthesis j_l

1960

1970 Year

1980

1990 2000

Figure 1.1. Milestones in pharmaceutical biotechnology.

realize hundred of millions of dollars or more in sales and their productivity, measured by revenue generated per employee, is comparable to that of large pharmaceutical companies (Table 1.1). A survey of top-selling biotechnology drugs identified four products (three different proteins) that have consistently achieved about one billion dollars in sales for at least four consecutive years (Table 1.2).

Biotechnology companies spend more than 20% of revenues in research and development (R&D). This is well above the 6% to 18% of revenue invested in R&D expenditure by large pharmaceutical companies (Table 1.1). The difference is due, at least in part, to the high cost of biotechnology research and perhaps to the intellectual climate at the relatively young, upstart biotechnology-based companies compared with that at the more established, large pharmaceutical companies. Given the rate at which new biotechnology-based pharmaceuticals are reaching the market and, in many cases, their therapeutic importance, it is essential for health care professionals and pharmaceutical researchers to understand the application of biotechnology to transform biological processes and entities into pharmaceuticals and other therapeutic modalities.

As we enter the information age, the availability of vast amounts of biological and genetic data, coupled with exponential growth in computing power, mean that the rate of developing novel biopharmaceuti-cals is no longer limited by the ability to identify targets and clone macromolecules. We have more targets than we can develop into pharmaceuticals. Therefore, drug candidate selection must be refined with experience gained in using macromolecules as therapeutic agents. We must focus on drug candidates that will be safe and effective and also have desirable clinical pharmacokinetic profiles. Compounds that exhibit high affinity binding to receptor targets but fail to penetrate target tissue, or do not persist there long enough to produce desirable biologic responses, cannot be considered for development as biopharmaceuticals.

■TABLE 1.1. Comparison of revenue, productivity, and market share between selective list of established biotechnology-based and large pharmaceutical companies

Revenue R&D Expenditure

Total

Per Employee

Total

% Revenue

Company

Employees

(in millions)

(in thousand)

(in millions)

Biotechnology companies

Amgen

6,400

$3,433

$536

$823

24

Genentech

3,880

$1,414

$364

$331

23

Biogen

1,350

$825

$611

$221

27

Genzyme

3,860

$777

$201

$156

20

Chiron

3,110

$684

$220

$254

37

Immunex

1,170

$559

$478

$127

23

Large pharmaceutical companies

Merck & Co

62,300

$32,762

$526

$2,119

6

Johnson & Johnson

97,800

$27,439

$281

$2,600

9

Bristol Myers Squibb

54,500

$20,199

$371

$1,843

9

Pfizer

51,000

$16,269

$319

$2,776

17

Glaxo Wellcome

55,273

$13,566

$245

$2,049

15

Eli Lilly & Co

31,300

$9,819

$314

$1,784

18

Source: Based on year 2000 data reported by Ernst & Young LLP, extracted from annual report of the listed companies.

Source: Based on year 2000 data reported by Ernst & Young LLP, extracted from annual report of the listed companies.

In this chapter, we will define biotechnology from the perspective of pharmaceuticals and follow this with a historical overview of pharmaceutical biotechnology and a discussion of how macromolecules are named and used as therapeutic agents.

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