Erythropoietic Molecules With Changes in Stability or Receptor Binding Activity

Endogenous EPO activates the EPORs on precursor red cells through homodimer-ization, whereby two receptor binding sites on a single EPO molecule crosslink two receptors (135). The two binding sites on rHuEPO have different affinities, high (approx. 1 nM) and low (approx 10 pM) (10). Initial binding is to the high-affinity binding site, followed by homodimerization of the receptor by binding to the low-affin ity binding site (9). Compounds that bind through the high-affinity site but do not dimerize because of reduced binding at the low-affinity site can function as antagonists (8). Such molecules may have clinical utility for treatment of rHuEPO-induced, secondary polycythemias, and several such molecules have been described (8,9).

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