THE PHARMACEUTICS AND DELIVERY OF THERAPEUTIC POLYPEPTIDES AND PROTEINS

Proteins and peptides with immunoregulatory properties are a rapidly g rowing class of pharmacophores for a wide variety of indications in a number of clinical disciplines. Despite the rapid development of these new drugs, they retain severe pharmacologic deficiencies due to their rapid degradation and elimination. This results in their administrati on at superpharmacological doses and subsequent clinical toxicity. Fur ther, because these compounds often act indirectly, their clinical dev elopment path is less obvious than that of other therapeutics. Thus, t heir development has become focused on a pharmacologic approach predic ated on the preclinical identification of therapeutic surrogates and t he subsequent testing of a clinical hypothesis. Immunoregulatory pepti des and proteins, including cytokines and growth factors, have been us ed as single agents and in combinations with one another or other ther apeutic modalities. Due to the challenge associated with the targeting and delivery of these therapeutics, novel strategies to achieve the d esired therapeutic endpoints have been developed. This includes the us e of peptide inducers or antagonists as well as delivery strategies vi a gene and cellular therapy. These therapeutic strategies of the futur e are in response to the pharmacologic deficiencies of proteins and pr ovide exciting new directions for their development in both the near a nd long term. This review addresses the pharmacologic deficiencies of proteins, preclinical and clinical developmental strategies, and futur e strategies based on the use of molecular therapeutics. The primary e mphasis has been placed on preclinical and clinical studies of immune and hematopoietic augmenting agents. However, we also discuss proteins that are still in animal models, agents whose profile of activity is associated with the induction of a cytokine cascade and the targeted d elivery of a gene via hematopoietic stem cells, lymphocytes, or other autologous tissues or tumors.