SYK inhibitor entospletinib prevents ocular and skin GVHD in mice
Jonathan C. Poe, Wei Jia, Julie A. Di Paolo, Nancy J. Reyes, Ji Yun Kim, Hsuan Su, John S. Sundy, Adela R. Cardones, Victor L. Perez, Benny J. Chen, Nelson J. Chao, Diana M. Cardona, Daniel R. Saban, Stefanie Sarantopoulos
Jonathan C. Poe, Wei Jia, Julie A. Di Paolo, Nancy J. Reyes, Ji Yun Kim, Hsuan Su, John S. Sundy, Adela R. Cardones, Victor L. Perez, Benny J. Chen, Nelson J. Chao, Diana M. Cardona, Daniel R. Saban, Stefanie Sarantopoulos
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Research Article Immunology Transplantation

SYK inhibitor entospletinib prevents ocular and skin GVHD in mice

Abstract

Graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation (HCT). The tyrosine kinase SYK contributes to both acute and chronic GVHD development, making it an attractive target for GVHD prevention. Entospletinib (ENTO) is a second-generation highly selective SYK inhibitor with a high safety profile. Potential utility of ENTO as GVHD prophylaxis in patients was examined using a preclinical mouse model of eye and skin GVHD and ENTO-compounded chow. We found that early SYK inhibition improved blood immune cell reconstitution in GVHD mice and prolonged survival, with 60% of mice surviving to day +120 compared with 10% of mice treated with placebo. Compared with mice receiving placebo, mice receiving ENTO had dramatic improvements in clinical eye scores, alopecia scores, and skin scores. Infiltrating SYK+ cells expressing B220 or F4/80, resembling SYK+ cells found in lichenoid skin lesions of chronic GVHD patients, were abundant in the skin of placebo mice but were rare in ENTO-treated mice. Thus, ENTO given early after HCT safely prevented GVHD.

Authors

Jonathan C. Poe, Wei Jia, Julie A. Di Paolo, Nancy J. Reyes, Ji Yun Kim, Hsuan Su, John S. Sundy, Adela R. Cardones, Victor L. Perez, Benny J. Chen, Nelson J. Chao, Diana M. Cardona, Daniel R. Saban, Stefanie Sarantopoulos

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Figure 10

Syk inhibition by ENTO selectively augments the apoptosis of B cells from patients with active cGVHD.

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Syk inhibition by ENTO selectively augments the apoptosis of B cells fro...
(A) PBMCs from patients with active cGVHD (n = 3, white circles) or no cGVHD (n = 3, black circles) were cultured for 48 hours in the presence of 2-fold increasing concentrations of ENTO ranging from 0.0078 to 1 μM. The cells were then harvested and analyzed by flow cytometry for the frequency of apoptotic B cells (CD19+Annexin V+ 7-AAD–). B cell apoptosis at each concentration is represented as the following ratio: %Annexin V+/7-AAD– B cells (ENTO treated)/%Annexin V+/7-AAD– B cells (untreated). Values are shown as mean with range. Statistical analysis comparing the ratios of apoptotic B cells between the active and inactive cGVHD groups was performed using a 2-tailed, unpaired Student’s t test (GraphPad Prism). (B) Graphic display and curve fit analysis with determination of the IC50 for ENTO apoptosis-inducing activity in active cGVHD B cells was performed using GraphPad Prism software on the active cGVHD B cell data in A. Values are shown as mean ± SEM. (C) The frequency of B cells, T cells, and monocytes from active cGVHD patients (n = 3) undergoing apoptosis in the presence of ENTO, across the concentration range described in A, that was above the frequency of apoptotic cells for each population treated with vehicle alone. Values are shown as mean ± SD. Statistical analysis was performed by 1-way ANOVA with Tukey’s multiple comparisons test (GraphPad Prism). *P < 0.05; **P < 0.01; ***P < 0.001.