RAP-536 Accelerates Recovery From Chemotherapy-Induced Anemia (CIA) without Promoting Tumor Growth In Murine Models of Cancer and CIA
Authors: Cadena Samuel M. , Suragani Rajasekhar NVS , Mitchell Dianne , Ucran Jeff , Liharska Katia , Sako Dianne , Monnell Travis , Underwood Kathryn , Kumar Ravindra , Pearsall R. Scott 
Published: October 2019

Abstract
Abstract 4230
We have previously shown that administration of ACE-536, a soluble form of a modified activin type IIB receptor, is an effective therapy in both acute and chronic animal models of anemia. We have further demonstrated that ACE-536 induces red cell development by promoting late stage erythroblast maturation.
Anemia is a debilitating complication associated with several chronic diseases, including cancer, and is exacerbated by the use of cancer chemotherapy. Recombinant human erythropoietin (EPO) is the most commonly prescribed treatment for chemotherapy induced anemia. However, there is increasing evidence to suggest that the administration of EPO may accelerate tumor growth by promoting angiogenesis. Therefore, non-EPO based strategies to correct chemotherapy induced anemia without effects on underlying tumor are needed. Several members of the TGF-β superfamily have been shown to be involved in red blood cell production. We have developed ACE-536 as a modified form of the extracellular region of the activin type IIB receptor fused to the Fc region of human IgG1, which binds to and inhibits several ligands in the TGF-β superfamily. Here we report on the effects of RAP-536, a murine analog of ACE-536 containing the modified extracellular region of the activin type IIB receptor fused to the Fc region of a murine IgG, in rodent models of chemotherapy induced anemia and tumor growth.
To evaluate the efficacy of RAP-536 in a rodent model of chemotherapy induced anemia 300 g Sprague-Dawley rats were administered a single intravenous dose of carboplatin (75 mg/kg) or phosphate-buffered saline (PBS). Blood samples were taken twice weekly to assess the induction of carboplatin induced anemia. By Day 11 rats treated with carboplatin showed an average drop of 34%, 32% and 36% in red blood cells, hemoglobin and hematocrit, respectively, and were randomized to receive RAP-536 twice weekly at a dose of 10 mg/kg or an equal volume of tris-buffered (TBS). Blood samples were taken twice weekly to evaluate recovery from anemia. Rats treated with RAP-536 exhibited a more rapid rate of recovery (ANOVA; P < 0.001) than those treated with TBS. Moreover, at study termination (Day 35), red blood cells, hemoglobin and hematocrit levels of RAP-536 treated rats were 28%, 23% and 23% greater, respectively, than TBS-treated controls (P < 0.01).
EPO administration has previously been shown to accelerate the rate of tumor growth in a mouse tumor bearing model; therefore, we sought to investigate the effect of RAP-536 in this context. Eight-week old mice were injected subcutaneously in the right hind flank with 3×105 Lewis lung carcinoma cells expressing a luciferase reporter. Mice were randomized to receive weekly subcutaneous injections of TBS, RAP-536 (10 mg/kg) or EPO (200 U/kg). Tumor growth was assessed twice weekly by manual external caliper measurements and once weekly by luciferase activity using an IVIS in vivo imaging system. Tumors in EPO treated mice grew at a moderately accelerated rate compared to TBS and RAP-536 treated mice; however, this was not statistically significant. At study termination tumors were excised and weighed. Mice treated with EPO showed statistically significant larger tumors compared to TBS treated animals (P = 0.0126). On the other hand, mice treated with RAP-536 did not show statistically significant increases in tumor size (P = 0.1689).
In conclusion, targeting the TGF-β signaling pathway with RAP-536 is a viable therapeutic approach for the treatment of anemia induced by chemotherapy treatment and may represent a safer alternative to EPO-based therapies.

Disclosures:
Cadena: Acceleron Pharma: Employment. Suragani:Acceleron Pharma: Employment. Mitchell:Acceleron Pharma: Employment. Ucran:Acceleron Pharma: Employment. Liharska:Acceleron Pharma: Employment. Sako:Acceleron Pharma: Employment. Monnell:Acceleron Pharma: Employment. Underwood:Acceleron Pharma: Employment. Kumar:Acceleron Pharma: Employment. Pearsall:Acceleron Pharma: Employment.