Therapeutic Effects of a NEDD8-Activating Enzyme Inhibitor, Pevonedistat, on Sclerodermatous Graft-versus-Host Disease in Mice Chien-Chun Steven Pai,

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Therapeutic Effects of a NEDD8-Activating Enzyme Inhibitor, Pevonedistat, on Sclerodermatous Graft-versus-Host Disease in Mice Chien-Chun Steven Pai, Lam T. Khuat, Mingyi Chen, William J. Murphy, Mehrdad Abedi Biology of Blood and Marrow Transplantation Volume 23, Issue 1, Pages 30-37 (January 2017) DOI: 10.1016/j.bbmt.2016.10.022 Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Time-dependent administration of pevonedistat produces differential scleroderma GVHD responses. Irradiated (8 Gy) BALB/c recipient mice underwent transplantation with BM cells with or without spleen cells (SP) from donor B10.D2 mice. Bortezomib was administered at day +20 and every 5 days thereafter, whereas pevonedistat was administered at the indicated times and every 5 days thereafter. (A) Scheme for pevonedistat or vehicle administration during cGVHD pathogenesis. (B) Representative pictures of mice that received BM cells only and BM cells and spleen cells with vehicle or pevonedistat from day +20. (C) Body weight changes among different regimen groups. (D) Survival rates in mice receiving BM only and BM cells and spleen cells with vehicle or pevonedistat from day +20. (E) Skin clinical score comparison among early therapy (from day +20) of bortezomib, pevonedistat, vehicle treatment, and BM-only groups. (F) Skin clinical score comparison among different pevonedistat administration times. Data, shown as mean ± SEM, were analyzed by 2-way ANOVA among individual groups. Data are representative of 2 independent experiments with 4 to 8 mice per group. Significant P values: *P < .05; ***P < .001; ****P < .0001. Biology of Blood and Marrow Transplantation 2017 23, 30-37DOI: (10.1016/j.bbmt.2016.10.022) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Histopathological analysis of mice that received pevonedistat treatment. Irradiated (8 Gy) BALB/c recipient mice underwent transplantation with BM cells with or without spleen cells (SP) from donor B10.D2 mice. Pevonedistat was administered i.p. at day +20 and every 5 days thereafter. Organs were harvested on day +59 after allo-HSCT. (A) Pathological examination of skin (upper) and GI tract (lower) by H & E stain. (B and C) Pathological scores for skin (on a scale of 0 to 10) and GI tract (on a scale of 0 to 4) were evaluated by pathologists in blinded fashion. Data, shown as mean ± SEM, were analyzed by 1-way ANOVA with a Tukey post hoc test to compare individual groups. Data are representative of 2 independent experiments with 3 to 4 mice per group. Significant P values: **P < .01; ***P < .001. Biology of Blood and Marrow Transplantation 2017 23, 30-37DOI: (10.1016/j.bbmt.2016.10.022) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Immune subsets after pevonedistat treatment. Irradiated BALB/c mice underwent transplantation with BM and spleen cells (SP) were injected with either pevonedistat (20 mg/kg) or vehicle control starting at day +20. Spleen cells were collected at +day 59 after allo-HSCT. All cell subsets were gated as Ly9.1- to distinguish donor-derived cells. (A) Total number of dendritic cells. (B) Total number of macrophages. (C) Total number of B cells. (D) Total number of plasma cells. (E) Total number of CD4 T cells. (F) Total number of CD8 T cells. The data, shown as mean ± SEM, were analyzed with the Student t test to compare individual groups. Data are representive of 2 independent experiments with 4 to 8 mice per group. Significant P values: *P < .05; **P < .01. N.S., nonsignificant. Biology of Blood and Marrow Transplantation 2017 23, 30-37DOI: (10.1016/j.bbmt.2016.10.022) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Comparison of T cell inhibition by bortezomib and pevonedistat. Splenocytes from resting BALB/c mice were plated in 96-well plates and stimulated with concanavalin A (2 µg/mL) for 24 hours (A) or 48 hours (B) with vehicle (10% 2-hydroxy-propyl-beta cyclodextrin), the dosage range of bortezomib, or pevonedistat. Cell proliferation was determined with the MTT assay kit following the manufacturer's instructions. Cell proliferation was measured by the optical density at a wavelength of 570 nm. The reference wavelength was 700 nm. The data, shown as mean ± SEM, were analyzed by 2-way ANOVA to compare individual groups. Significant P values: *P < .05; **P < .01; ****P < .0001. Biology of Blood and Marrow Transplantation 2017 23, 30-37DOI: (10.1016/j.bbmt.2016.10.022) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 The impact of pevonedistat administration on cGVHD and GVT in the A20 tumor model. Irradiated BALB/c mice underwent transplantation with BM cells with or without spleen cells (SP) at day 0. A20 luciferase-transfected lymphoma cells (1 × 106) were injected through the tail vein into the indicated groups at day +20. Pevonedistat was also administered at day +20 and every 5 days thereafter. (A) Timeline schema for different conditions among groups. (B) Bioluminescence images acquired to monitor tumor burdens. (C) Quantification of tumor burden by bioluminescence signals. (D) Body weight changes after allo-HSCT. (E) Skin clinical scores were evaluated twice weekly. Data were collected from 1 experiment with 8 mice per group. The data, shown as mean ± SEM, were analyzed by 2-way ANOVA for comparisons among individual groups. Significant P values: ***P < .001; ****P < .0001. N.S., nonsignificant. Biology of Blood and Marrow Transplantation 2017 23, 30-37DOI: (10.1016/j.bbmt.2016.10.022) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions