Biology Reference
In-Depth Information
New molecules and formulations of recombinant
human erythropoietin
Steven G. Elliott
Amgen Inc., One Amgen Center Drive, M/S 29-1-A, Thousand Oaks, CA 91320, USA
Introduction
Recombinant human erythropoietin (rHuEPO), is a glycoprotein hormone
commonly used for the treatment of anemia associated with chronic kidney
disease [1-3]. It is also indicated for the treatment of anemia associated with
cancer, human immunodeficiency syndrome virus (HIV) infection, and for use
in surgical situations to reduce allogeneic blood transfusion requirements. (For
further information see Chapters 9, 10, 11, and 12). A number of studies have
shown that rHuEPO is well tolerated and effective at ameliorating anemia,
restoring energy levels, and improving patient quality of life in these indica-
tions. The clinical benefits of rHuEPO are well understood and appreciated.
The endogenous EPO protein is naturally optimized for maintenance of
hemostasis in the body where the protein can be produced on demand in the
amounts needed. However, that which is optimal for natural
in vivo
production
may be sub-optimal in the context of clinical intervention. For example,
rHuEPO must be administered frequently by injection to be efficacious. The
discomfort of injections and the inconvenience to the patient and healthcare
provider burdens both groups.
Approaches to enhancing a drug's properties have included new formula-
tions and delivery systems of the existing drugs whereby the circulating con-
centration of the drug is maintained for extended periods of time (sustained
delivery). Such improvement can be accomplished in several ways, including
use of pumps or slow-release formulations. Alternatively, proteins can be mod-
ified chemically with attached polymers that confer a longer half-life (sus-
tained duration of action). Attempts to modify the protein itself by
in vitro
mutagenesis or through protein fusions to other peptides or protein hormones
have been explored. Glycoengineering has been successfully applied to
rHuEPO. With this process, new carbohydrate attachment points are intro-
duced into the protein, increasing the amount of attached carbohydrate and
increasing
in vivo
activity and serum half-life without substantially lowering
in
vitro
activity. The new molecule can be administered with extended dosing
intervals with no loss of efficacy.
