Murine TGFβ-antagonist (RAP-1332) Inhibits Fibrosis in a Murine Model of Myelofibrosis. Rajasekhar NVS Suragani, PhD
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1 Murine TGFβ-antagonist (RAP-1332) Inhibits Fibrosis in a Murine Model of Myelofibrosis Rajasekhar NVS Suragani, PhD
2 Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) Mutations leading to constitutively active signaling and uncontrolled proliferation of BM myeloid lineage cells and ultimately cause fibrosis Janus Kinase2 (JAK2) V617F mutation: 95% in PV, ~5-6% in ET and PMF PV ET PMF Calreticulin (CALR): 2-25% in ET and PMF Myeloproliferative leukemia virus (MPL) oncogene: less than 1% for ET and PMF Post-PV Post-ET Central role of TGFβ signaling pathway in fibrosis 1 Myelofibrosis Murine model of MPN: JAK2(V617F) transgenic expression 2 Elevated RBC (PV), elevated platelets (ET), elevated WBC with progression into Myelofibrosis with age Splenomegaly; mean survival age of ~17 months 1 Rosemary JA et al., Nature Reviews (212) 2 Shu Xing et al., Blood (28)
3 Outline TGFβ expression and initiation of fibrosis in the JAK2(V617F) murine model Treatment of TGFβ antagonist (ACE-1332) in JAK2(V617F) transgenic mice Combination treatments of RAP-1332 and ruxolitinib (JAK2 inhibitor) in JAK2(V617F) transgenic mice
4 WBC (1 3 cells/μl) Platelets(1 3 /μl) RBC (1 6 cells/μl) Spleen weight (mg) JAK2(V617F) transgenic mice display elevated RBC, Platelets, WBC and splenomegaly RBC 2 15 Spleen weight Wild type JAK2(V617F) Wild type JAK2(V617F) 16 WBC B2 wt wt 4B wt 6B Platelets wt 7B JAK 2-2M JAK2-3M JAK2-4B JAK2-5M JAK2-8M JAK2-1M JAK2-12M Wild type Age (months) JAK2(V617F) Wild type Age (months) JAK2(V617F)
5 BM Fibrosis starts in JAK2(V617F) transgenic mice at 5-months and worsens with age Fibrosis (Reticulin, 2x) Age (months)
6 pg/ml Serum levels of TGFβ1 and 3 but not TGFβ2 ligands are elevated in JAK2(V617F) transgenic mice pg/ml pg/ml pg/ml pg/ml 1 TGFβ1 TGF 2 TGFβ2 TGF 3 TGFβ3 TGF WT 2 mos Wild type WT 6 mos JAK2 2mos JAK2 5mos JAK2(V617F) JAK2 8mos Age (months) 6 JAK2 1mos JAK2 12mos TNFalpha TNFα WT 2 mos Wild type JAK2(V617F) Age (months) WT 6 mos JAK2 2mos JAK2 5mos JAK2 8mos 4 JAK2 1mos JAK2 12mos IL-6 IL-6 WT 2 mos Wild type JAK2(V617F) Age (months) WT 6 mos JAK2 2mos JAK2 5mos JAK2 8mos JAK2 1mos JAK2 12mos WT 2 mos Wild type JAK2(V617F) Age (months) WT 6 mos JAK2 2mos JAK2 5mos JAK2 8mos JAK2 1mos JAK2 12mos WT 2 mos Wild type JAK2(V617F) Age (months) WT 6 mos JAK2 2mos JAK2 5mos JAK2 8mos JAK2 1mos JAK2 12mos
7 ACE-1332 binds tightly to TGFβ1 and TGFβ3 ligands but not to TGFβ2 ACE-1332 is a protein biologic engineered to bind and inhibit signaling by TGFβ1 and TGFβ3 but not TGFβ2 Does not bind other ligands in the TGFβ-superfamily RAP-1332 is murine ortholog of ACE-1332 RAP-1332 TGFβ1 TGFβ2 TGFβ3 Ligands Biacore K D 37 o C Cell Based Assay IC 5 (ng/ml) A549 RGA TGFβ TGFβ2 4 No Inhibition TGFβ
8 Study design: Treatment of JAK2(V617F) transgenic mice with TGFβ antagonist (RAP-1332) Genotype Sex Age (Mos) N Treatment Dosage Frequency Duration (months) Wt M 4 15 TBS JAK2(V617F) M 4 15 TBS Iso volume Iso volume JAK2(V617F) M 4 15 RAP mg/kg Twice weekly Twice weekly Twice weekly 3, 6 3, 6 3, 6 Treatment initiated before the onset of fibrosis
9 RAP-1332 treatment for 3 months reduced fibrosis in BM and Spleen (JAK2 V617F mice) JAK2 + VEH JAK2 + RAP-1332 BM Spleen 9 Age of mice at study termination: 7 months
10 RAP-1332 treatment for 6 months reduced fibrosis in BM and Spleen in JAK2 (V617F) transgenic mice JAK2 + VEH JAK2 + RAP-1332 BM Spleen Age of mice at study termination: 1 months
11 WBC (1 3 cells/ml) RBC (1 6 cells/ml) Plt (1 3 /ml) RAP-1332 treatment for 6 months reduced splenomegaly in JAK2(V617F) mice 2 16 RBC Platelets 12 8 Wt Time (weeks) WBC JAK2+VEH JAK2+RAP Time (weeks) Spleen weight -29.% * * Time (weeks) Wt JAK2(V617F) + VEH JAK2(V617F) + RAP-1332 ** p<.1 vs VEH
12 RAP-1332 treatment reduced erythroid hyperplasia in Spleen and serum IL-6 levels in JAK2(V617F) mice after 6 months treatment Wt JAK2+VEH JAK2+RAP-1332 TER Spleen # # # * Wt JAK2+VEH JAK2+ RAP-1332 # # # -48.9% ** Wt JAK2+VEH JAK2+ RAP-1332 # # # p<.1 vs Wt; **p<.1, *p<.5 vs JAK2+VEH
13 Combination treatment of RAP-1332 and Ruxolitinib in JAK2(V617F) transgenic mice(12 months old) Genotype Sex Age (Mos) N Treatment Dosage Frequency Duration (weeks) JAK2(V617F) M 12 9 veh Iso volume JAK2(V617F) M 12 1 RAP mg/kg Twice weekly Twice weekly 3 3 JAK2(V617F) M 12 1 Ruxolitinib 6 mg/kg Twice daily 3 JAK2(V617F) M 12 1 Ruxolitinib + RAP-332 6/1 mg/kg Twice daily/twice weekly 3 Treatment initiated at late stage of disease
14 RAP-1332 or Combination treatment with Ruxolitinib reduced BM fibrosis in JAK2(V617F) transgenic mice VEH Ruxolitinib 3-week treatment RAP-1332 Ruxolitinib + RAP
15 WBC (1 3 cells/μl) RBC (1 6 cells/μl) Plt (1 3 cells/μl) Ruxolitinib or combination treatment with RAP-1332 reduced RBC and splenomegaly in JAK2(V617F) transgenic mice ** RBC * *** Platelets WBC 3-week treatment Spleen weight % -26.4% * P<.5; ** P<.1; *** P<.1 vs VEH
16 Summary In the JAK2(V617F) transgenic mouse model of myelofibrosis, bone marrow fibrosis starts at 5 months and worsens with age Expression of TGFβ1 and TGFβ3 ligands were elevated in JAK2(V617F) transgenic mice consistent with the initiation of fibrosis ACE-1332, a protein biologic ligand trap inhibits specific signaling by TGFβ1 and TGFβ3 ligands but not by TGFβ2 or the other members of the family Treatment with RAP-1332 before the onset of fibrosis reduced splenomegaly and erythroid hyperplasia inhibited fibrosis in BM and spleen decreased inflammatory cytokine levels in serum Combination treatment of RAP-1332 and ruxolitinib decreases fibrosis compared to ruxolitinib monotherapy while retaining the beneficial effects of decreasing splenomegaly
17 Acknowledgements Pedro Martinez, PhD Robert Li Scott Pearsall, PhD Ken Attie, MD Matt Sherman, MD Steve Ertel, MBA Ravi Kumar, PhD Acceleron Team! 17
18 WBC (13 cells/μl) Spleen wt (mg) RBC (1 6 cells/μl) Plt (1 3 /μl) RAP-1332 treatment did not effect RBC, WBC and Platelets or splenomegaly in JAK2(V617F) mice after 3 months of dosing RBC 12 8 Platelets N=5/group 4 3 WBC 8 6 Spleen wt
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