Targeting Epo to treat anemia

1. Annalisa M. VanHook
+ Author Affiliations

Sci. Signal.  17 May 2016:

Vol. 9, Issue 428, pp. ec113
DOI: 10.1126/scisignal.aag1311
 Article
 Info & Metrics
 eLetters

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 (EPO R150A) 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 EPO R150A. 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-EPO R150A stimulated only RBC production.
Pharmacokinetic analysis showed that the majority of injected 10F7-EPOR150A bound to erythrocytes instead of persisting in the plasma. Although EPO R150A 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]