ACE-536, a Novel, GDF-Trap, Promotes Rapid Increase of Red Blood Cells In Vivo in An EPO-Independent Manner.

Abstract 2505

Poster Board II-482

Anemia is a common and debilitating complication associated with cancer chemotherapy, which depletes and prevents formation of red blood cells, and leads to incapacitating fatigue. The most common treatment for anemia involves administering recombinant erythropoietin (EPO); however, there are limitations with this form of therapy. A significant number of patients exhibit resistance to EPO treatment and several studies suggest in some cases EPO treatment can worsen patients' outcomes. Consequently, novel, non-EPO based therapeutics for anemia are needed. Several members of the TGF-β superfamily have been described to play a role in erythropoiesis. We developed ACE-536, a novel, GDF trap derived from the Type II activin receptor fused to the Fc region of IgG1, which binds to and inhibits several ligands in the TGF-β superfamily, and studied its effect on erythrocyte development.

In vivo subcutaneous administration of ACE-536 (10mg/kg, or an equal volume of TBS vehicle control) in mice twice weekly resulted in significant increases of 6–9% in hematocrit, hemoglobin content, and red blood cell (RBC) count (P < 0.01) over the vehicle-only group after 4 days, although these blood parameters were already significantly increased 24 hours post-treatment. These observations were seen even in the presence of an EPO neutralizing antibody suggesting that EPO is not directing the initial RBC response. Moreover, it was shown that in this same 4 day period, treatment with ACE-536 did not result in altered EPO mRNA or protein expression, suggesting this drug acts independently of EPO. Furthermore, ACE-536 treatment resulted in a two-fold increase in CFU-E erythrocyte precursor populations in the spleen compared to the vehicle-only group, with no significant alterations in the levels of BFU-E precursor numbers. Gene array studies were used to characterize the mechanism by which ACE-536 alters erythropoiesis, and demonstrated that ACE-536 reduced the expression of numerous genes involved in erythroid differentiation. Thus, by delaying terminal differentiation, ACE-536 enables late-stage, erythroid progenitors to undergo addition cycles of proliferation, ultimately leading to the rapid increase in mature red blood cells. In conclusion, this study provides evidence that ACE-536 promotes development of red blood cells via an EPO-independent mechanism, and may prove to be an effective alternative to EPO therapy for patients suffering from anemia.