Editors' ChoiceDRUG DESIGN

Targeting Epo to treat anemia

Sci. Signal.  17 May 2016:
Vol. 9, Issue 428, pp. ec113
DOI: 10.1126/scisignal.aag1311

Recombinant forms of the protein hormone erythropoietin (EPO) are used to treat some types of severe anemia because EPO stimulates red blood cell (RBC) precursors to differentiate into mature RBCs. However, the EPO receptor (EPO-R) is also present on platelet-producing megakaryocytes and on some tumor cells, so this treatment confers an increased risk of thrombosis and may promote tumor progression. Burrill et al. engineered a form of EPO that activates EPO-R specifically on RBC precursors, but not on other cell types. The antibody 10F7 binds to the extracellular domain of human glycopohorin A (huGYPA), which is an abundant transmembrane protein that is restricted to the RBC lineage. The authors fused the sequence encoding the variable fragment of this antibody plus a 35–amino acid linker to wild-type EPO and to a mutant form of EPO (EPOR150A) that binds poorly to EPO-R. In vitro, 10F7-EPOR150A readily dissociated from EPO-R, but in cultured erythroleukemia cells, 10F7-EPOR150A stimulated proliferation as well as wild-type EPO or 10F7-EPO and better than EPOR150A. Whereas 10F7-EPO stimulated the proliferation of EPO-R–positive tumor cell lines, 10F7-EPOR150A did not. In mice expressing huGYPA, a single intraperitoneal injection of 10F7-EPO or a commercially available synthetic form of EPO stimulated the production of both RBCs and platelets, but injecting the same dose of 10F7-EPOR150A stimulated only RBC production. Pharmacokinetic analysis showed that the majority of injected 10F7-EPOR150A bound to erythrocytes instead of persisting in the plasma. Although EPOR150A is a rather poor stimulator of EPO-R, targeting it to erythrocytes enables sufficient signaling to selectively stimulate these cells to proliferate. Because many signaling molecules affect multiple types of cells, similar engineering strategies to create forms that are tissue- or cell type–specific may permit the development of therapies that deliver a benefit while reducing or eliminating undesirable side effects.

D. R. Burrill, A. Vernet, J. J. Collins, P. A. Silver, J. C. Way, Targeted erythropoietin selectively stimulates red blood cell expansion in vivo. Proc. Natl. Acad. Sci. U.S.A. 113, 5245–5250 (2016). [PubMed]

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