Pedro A. Martinez, PhD December 7 th, 2015
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1 RAP-536 (Murine ACE-536/Luspatercept) Inhibits Smad2/3 Signaling and Promotes Erythroid Differentiation By Restoring GATA-1 Function in Murine β-thalassemia Pedro A. Martinez, PhD December 7 th, 2015
2 Outline Background Mechanism of ACE-536 Ligand binding profile Molecular Targets RNA-seq analysis GATA1 negative regulation via GDF11 Conclusions
3 ACE-536 (Luspatercept) is a Modified ActRIIB Receptor Fusion Protein ACE-536 is a fusion protein that consists of a modified activin receptor (ActRIIB) - a member of the TGFβ superfamily - and the Fc of human IgG1 Inhibits Smad2/3 signaling and acts as a ligand trap Robust stimulation of RBC production in mice, rat and cynomolgus monkeys ACE-536 Modified Extracellular Domain of ActRIIB Fc Domain of human IgG 1 Antibody Co-developed with Celgene RAP-536 is murine ortholog of ACE-536
4 Effect of ACE-536 (Luspatercept) on Erythropoiesis ACE-536 treatment increases RBCs however activity is distinct from EPO Effect is focused on the differentiation of erythroid precursors while EPO affects proliferation of BFU-E and CFU-E ACE-536 promotes differentiation of Baso, Poly, and Ortho Erythroblasts ACE-536 does not affect other cell lineages ACE-536 has corrected anemia in various murine preclinical models of ineffective erythropoiesis such as MDS and β-thalassemia Suragani et al., Nature Medicine 2014
5 RAP-536 decreases elevated psmad2/3 and attenuates anemia in a murine model of β-thalassemia (Hbb -/- ) RBC EPO Reticulocytes * 5 WT th1/th1 th1/th1 + RAP-536 WT th1/th1 th1/th1 + RAP-536 th1/th1 th1/th1 + RAP-536 # # # p< vs wt; ** p< 0.01, *p<0.05 vs th1/th1 Suragani et al., Blood 2014
6 RAP-536 corrects Ineffective Erythropoiesis and associated co-morbidities in a β-thalassemia mouse model (Hbb -/- ) Improved Bone Mineral Density Decreased Liver Iron WT β-thal+tbs β-thal+rap-536 Reduced Spleen Size WT β-thal+tbs β-thal+rap-536 Improved RBC Morphology 6 WT βthal+tbs βthal+rap-536 βthal+tbs βthal+rap-536
7 RAP-536 decreases elevated psmad2/3, attenuates anemia and decreased erythroid hyperplasia in a mouse model of MDS psmad2/3 Hgb 7 Suragani et al., Nature Medicine 2014 *p< 0.05 vs MDS+TBS ### p< vs WT+TBS
8 ACE-536(Luspatercept) inhibits Smad2/3 signaling ligands Smad2/3 signaling Ligands Biacore K D 37 o C ACE-536 Cell Based Assay IC 50 (ng/ml) A204 RGA GDF GDF Activin B 0.27 >14,400 Activin A No binding >33,000 TGF-b1 No binding >33,000 8
9 GDF11 (pg/ml) GDF11 (pg/ml) Elevated levels of serum GDF11 detected in patients with MDS and β-thalassemia * Normal sera MDS sera Normal: 6 MDS patients: 8 Normal sera β-thalassemia sera Normal: 5 Thalassemia patients: 19 9 * p< 0.05
10 RBC (10 6 cells/ml) Hgb (gm/dl) GDF11 and other Smad2/3 ligands contribute to the activity of Luspatercept Red Blood Cells Hemoglobin *** ** *** *** VEH RAP-536 Anti-activin B Anti-GDF8/11 Anti-actB + mab Anti-GDF8/11 13 VEH RAP-536 Anti-activin B Anti-GDF8/11 Anti-actB + mab Anti-GDF8/11 10 Dosage: 10mg/kg, twice/week for 2 weeks, N= 5/group ** P<0.01, *** P< vs VEH
11 Flow cytometric cell sorting of β-thalassemic erythroid precursors (basophilic) for RNA sequencing analysis CD71 + Ter119 + Fsc high (Basophilic erythroblasts) 11 β-thalassemic mice were treated with VEH or RAP-536 Splenic basophilic erythroblasts were sorted via flow post 16hrs treatment RNA was isolated from these cells for RNA-seq
12 Differentially regulated genes by RAP-536 treatment in β- thalassemic erythroid precursors VEH RAP genes were differentially expressed by RAP-536 (absolute fold change >1.5, FDR P-value <0.05) Upregulated pathways: Respiratory Electron Transport Oxidative phosphorylation Porphyrin Metabolism Proteasomal Pathway Downregulated IL-12 12
13 Gene Set Enrichment Analysis (GSEA)-Transcription Factors Transcription Factors Enrichment Score HSF_Q GATA_C NEF2_ Unbiased enrichment analysis - GATA1, NEF2, and HSF transcription factors are activated while NfκB, etc., are repressed 158 GATA1 downstream targets were differentially upregulated by RAP-536 treatment 13
14 GATA-1 transcription factor downstream target genes are differentially regulated by RAP-536 treatment RAP-536 VEH Pathways Expression Genes Erythroid differentiation Heme biosynthetic pathway Protein quality control Up Up Up Gata1, Fog1, p21, Klf1, Hri, Atf4, Bcl-xl, Alas2, Abcb6, Ppox, Mthfr, Bach1, Fech Nqo1, Prdx2, Sod2, Hsp s, Psmc3 Proliferation and cell death Down Fos, Jun, Igf1r These data indicate that psmad2/3 negatively regulates erythropoiesis 14
15 Control GDF-11 GDF-11 + ACE-536 Mouse erythroid leukemic (MEL) and murine primary fetal liver erythroid cells as a model Differentiating erythroid cells (MEL cells treated with DMSO) or Fetal liver cells Fetal liver erythroid cells GDF11 Phosphorylation of Smad2/3 GATA1 availability MEL Reactive Oxygen Species What is the role of ACE-536 psmad2 60kDa GAPDH 37kDA 15 GDF11(100 ng/ml -1 ), 30 mins
16 GATA1 levels are decreased in the nucleus with GDF11 treatment ACE-536 reverses this effect in MEL cells 16 Control GDF11 GDF11 ACE-536 GATA1
17 MFI - GATA1 GATA1 levels are decreased in the nucleus with GDF11 treatment ACE-536 reverses this effect in MEL cells Control GDF11 GDF11 ACE-536 * DAPI GATA1 HSP70 17 Control GDF11 GDF11 + ACE-536
18 GATA1 levels are decreased in the nucleus with GDF11 treatment ACE-536 reverses this effect in MEL cells DAPI GATA1 HSP70 Control GDF11 GDF11 ACE-536 Nuclear extract 18
19 GATA1 levels are decreased in the nucleus with GDF11 treatment ACE-536 reverses this effect in murine fetal liver erythroid precursors Control GDF11 GDF11 ACE GATA1
20 β-thalassemia + ACE-536 β-thalassemia GATA1 levels are restored in the nucleus of β-thalassemic murine BM cells GATA1 DAPI Merge 20
21 ROS is induced with GDF11 treatment and reduced upon cotreatment with ACE-536 in MEL cells GDF11 GDF11 + ACE536 21
22 Model - β-thalassemia GDF11 = Erythroid differentiation is inhibited ROS psmad2/3 C-Cas-3 Nucleus GA TA1 22
23 Model - β-thalassemia + ACE536 GDF11 ACE-536 ROS = Block removed Proper erythroid maturation psmad2/3 C-Cas-3 Nucleus GATA1 23
24 Conclusions Luspatercept (ACE-536) binds and inhibits signaling by certain Smad 2/3 signaling ligands RNA seq analysis revealed that ACE-536 upregulates genes involved in erythroid differentiation through GATA1 GDF11 increases ROS and limits the availability of GATA1 in the nucleus ACE-536 decreases ROS and restores GATA1 availability Luspatercept is currently being tested in patients with β-thalassemia 24 and MDS
25 25 Acknowledgements Dr. Suragani Dr. Kumar Dr. Bhasin Collaborator at Beth Israel Medical Center at Harvard Dr. Attie Dr. Sherman Steve Ertel Acceleron Team Celgene Team
Pedro A. Martinez, PhD June 10 th, 2016
(Murine ACE-536/Luspatercept) Inhibits Smad2/3 Signaling and Promotes Erythroid Differentiation By Restoring GATA1 Function in Murine β-thalassemia Pedro A. Martinez, PhD June 10 th, 2016 ACE-536 is a
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