Large Molecule Biopharmaceutical Drugs

To date, most approved protein-based drugs are for therapeutic or replacement therapies. They are recombinant versions of natural proteins such as insulin and erythropoietin. Their characteristics and functions are relatively well defined and known. The next phase of biopharmaceuticals, such as antibodies and vaccines, is more complex and requires more tests and characterizations. Controls for the reliability, contamination, and fidelity of expression systems will be high on the agenda in the coming decade. 

Angiotensin converting enzyme (ACE) is an important enzyme for the regulation of blood pressure, ft exists in two forms the somatic form has 1277 amino acids, while the sperm cell form has 701 amino acids. The somatic form consists of two domains the carboxy-terminal (C) domain and the amino-terminal (N) domain. The sperm cell form consists of only the C domain. Studies have shown that the C domain is the dominant angiotensin converting site for controlling blood pressure and cardiovascular functions. 

The structure with an inhibitor, lisinopril, revealed the exact nature of the binding of the drug to the active site. With this detailed analysis, more efficacious drugs are expected to be developed to bind to the active site (C terminal, such as RXPA380) and control blood pressure. 

Sources (1) Natesh R, Schwager SL, Sturrock ED, Acharya KR. Crystal structure of the human angiotensin-converting enzyme-lisinopril complex, Nature 421 551-554 (2003). Used with permission. (2) Turk B. Targeting proteases, successes, failures and future prospects. Nature Reviews Drug Discovery 5 785-799 (2006). 

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Most small molecule drugs are formulated for oral delivery while large molecule biopharmaceuticals are injected via parenteral means intravenous, intramuscular, subcutaneous, and infusion. 

Table 1.2 shows the top 10 drugs in 2006 with the exception of Enbrel (a biopharmaceutical, large molecule drug—see Chapter 4), all the others are... 

Unlike the small molecule drugs (pharmaceuticals) described in Chapter 3, large molecule drugs (biopharmaceuticals) are mainly protein based. Another distinction is that these protein-based drugs are, in the main, similar to natural biological compounds found in the human body or they are fragments that mimic the active part of natural compounds. 

Comparison of Preclinical Development Programs for Small Molecules (Drugs/Pharmaceuticals) and Large Molecules (Biologics/Biopharmaceuticals) Studies, Timing, Materials, and Costs... 

For the purposes of this discussion, drugs are chemically synthesized pharmaceuticals, often described as small molecules or new chemical entities biologies are large molecules or biopharmaceuticals. ... 

The biopharmaceutical industry for producing large molecule protein-based drugs has grown exponentially in the past 25 years (Exhibit 11.3). 

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