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 1

Orally administered ENTO reaches expected therapeutic range as assessed in pharmacokinetic studies.

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Orally administered ENTO reaches expected therapeutic range as assessed ...
(A) 7 days after ENTO initiation, representative mice from HCT groups fed either 0.02% ENTO or 0.06% ENTO were bled at 8-hour intervals over a 24-hour period, and plasma was assessed for ENTO levels (performed by Agilux Laboratories Inc.). Each symbol represents an individual mouse (blue, 0.02% dose; red, 0.06% dose). Error bars represent the mean ± SD. Average ENTO levels for each dose over the entire 24-hour time period are indicated by the colored dashed lines (0.02% ENTO, blue; 0.06% ENTO, red). Calculated EC70 and EC50 values derived from a standardized in vitro SYK inhibition assay (41) are as indicated by the gray dashed lines. 0.02% ENTO groups consisted of +Spl mice only. 0.06% ENTO groups consisted of both +Spl mice (asterisks) and BM-only mice (crosses). (B) Bars indicate the median ± range chow consumption per mouse (grams/day) in each HCT group over the first 7 days following ENTO initiation. Each symbol represents the average values for mice housed in an individual cage, with 2 cages per group in the study. (C) All mice in each HCT group (n = 9–10 mice/group at day 0) were weighed over time on the days indicated by symbols in each graph. Values represent mean ± SEM percentage of body weight on the day indicated compared with the weight on the day that HCT was performed (day 0). ENTO administration was initiated on day +12. The arrow indicates the time (day +54) after which only 1 mouse in the +Spl/placebo group remained alive, and so no further weight tracking is shown for this group.