Medicinally useful proteins--enhancing the probability of technical success in the clinic

Proteins that are normally present in organisms function to maintain the overall homeostatic balance of the living system. Although an understanding of the biology of these proteins is essential to determining their utility in the treatment of disease, the administration of wild-type forms of proteins in a therapeutic manner (often systemically and at concentrations much higher than those found in the healthy organism) can have the effect of inappropriate activation of cell types and compartments that can lead to an undesirable response. Modification of the sequence of the parent protein to yield selected biological properties can generate derivative versions (muteins) having an optimal therapeutic profile. In addition to consideration of the biological properties, protein therapeutics are typically not active when delivered orally. This can limit the frequency with which the therapeutic agent can be administered to the patient, exemplifying the need to understand the pharmacokinetic and pharmacodynamic relationships of the protein. The biophysical properties of the mutein (e.g., solubility and stability) must also be considered in this context. An additional consideration with therapeutic proteins, engineered or not, is the potential immune response resulting from sequence variation and/or exogenous presentation to the immune system. The composite application of these principles to therapeutic protein discovery and development drives the ultimate success of any given biopharmaceutical agent.