Biology Reference
In-Depth Information
The inherent limitations of rHuEPO due to its peptidic composition or
mechanism of action can potentially be bypassed entirely with new molecular
entities such as small molecules or antibodies (EPO mimetics). These com-
pounds may have advantageous biological or chemical properties not present
in rHuEPO, such as an oral route of delivery, (small molecule), or structural
conformations that hold little in common with EPO, thus exploiting different
routes of elimination. Finally,stimulation of erythropoiesis by mechanisms
different from those of rHuEPO, such as those steps upstream or downstream
from receptor activation step, have been attempted. This chapter discusses new
molecules being considered or developed and their limitations, if any.
Considerations of new formulations and drug entities
The purpose of any therapeutic intervention is to treat the patient without caus-
ing harm, and rHuEPO has been particularly successful in this regard. The
molecule is very effective at stimulating erythropoiesis with minimal side-
effects. This excellent safety profile has created a high standard against which
any new erythropoiesis-stimulating molecule will be measured. Not only
should a new drug entity have improved properties, but it should also match
the excellent safety profile of rHuEPO. The preferred properties of any new
drug or formulation include retention or increase in efficacy and lack of new
or unwanted side-effects or toxicities.
One particular concern is anti-EPO antibodies [4]. (See Chapter 14 for fur-
ther information.) Antibody formation to new drug entities is important not
only because the drug may lose efficacy, but also because such antibodies
might cross-react with endogenously produced EPO resulting in pure red cell
aplasia, a very serious and severe form of anemia. Potential causes for anti-
body formation not only include the structure of the molecule itself, but also
the breakdown products or aggregates generated during manufacturing or stor-
age. Accordingly, new drugs should be designed and manufacturing proce-
dures put in place to minimize this risk.
EPO molecules with altered activity
One approach to increase activity of EPO is to alter the interaction with the
EPO receptor (EPOR). EPO activates erythroid precursor cells by binding and
activating EPOR on the surface of erythroid progenitor cells [5]. (See
Chapters 3 and 5 for further discussion.) Receptor activation occurs through
homodimerization, whereby the two EPOR binding sites on a single EPO
molecule crosslink two EPOR [6]. The two binding sites on rHuEPO have dif-
ferent affinities, high (approximately 1 nM) and low (approximately 10 µM)
[7]. Initial binding is to the high-affinity binding site, followed by homod-
imerization of the receptor by binding to the low-affinity binding site [8].
