Protein mode of action and pharmacodynamics

Different protein therapeutics bring about their therapeutic effect in different ways (Figure 4.8). Hormones and additional regulatory molecules invariably achieve their effect by binding to a specific cell surface receptor, with receptor binding triggering intracellular signal transduction event(s) that ultimately mediate the observed physiological effect(s). Many antibodies, on the other hand, bring about their effect by binding to their specific target molecule, which either inactivates/triggers destruction of the target molecule or (in the case of diagnostic applications) effectively tags the target molecules/cells. Therapeutic enzymes bring about their effect via a catalytic mechanism. The mode of action of many specific biopharmaceuticals will be outlined in

Table 4.3 Therapeutic proteins engineered in some way in order to alter pharmacokinetic or other pharmacological characteristics. Full details of specific products are provided in the chapter indicated


Engineering detail/rationale


Chimaeric and humanized antibodies

Engineered tPA Fast-acting insulins

Long-acting insulins

PEGylated interferons

PEGylated Macugen Carbohydrate-remodelled EPO

Carbohydrate-remodelled glucocerebrosidase

Rendering murine antibodies more human in sequence, 13

thereby decreasing their immunogenicity and increasing their serum half-life Increasing serum half-life, allowing administration by a 12

single i.v. injection as opposed to infusion over 90 min Amino acid substitutions generate products that enter the 11

bloodstream more quickly from the site of injection, facilitating product co-administration with a meal rather than administration 30-45 min prior to a meal Amino acid substitutions generate a product that enters 11

the bloodstream very slowly from the site of injection, thereby maintaining basal insulin blood levels over an extended period

Covalent attachment of PEG increases interferon half-life 8

from 3 h to some 24 h, thereby generating a product whose dosage schedule requires once-weekly as opposed to daily administration PEGylation increases the molecular weight of this aptamer 14

from about 10 kDa to some 50 kDa, thereby increasing its half-life in the vitreous humor EPO displaying additional sugar side chains, increasing its 10

plasma half-life and thereby facilitating a once-weekly as opposed to three-times weekly injection schedule Enzymatic removal of sialic acid caps exposes mannose 12

residues, triggering selective product uptake by macrophages (the target cell type)

Chapters 8-14; however, it is important to note that the exact molecular detail underpinning the effects of many such drugs has not been fully characterized.

A significant element of preclinical studies, therefore, centres upon identification of a drug's mode of action at a molecular level, in addition to investigating the full range of resultant physiological effects. Pharmacodynamic studies will invariably include monitoring effects (and the timing of effects) of the therapeutic protein at different known drug concentrations and drug delivery schedules.

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