Soluble Siglec-8 Levels Are Detectable In Subjects With Myeloid Variant Hypereosinophilic Syndromes, But Not In Those With D816V KIT+ Systemic Mastocytosis
Monday, March 5, 2018
South Hall A2 (Convention Center)
Fanny Legrand, PhD PharmD, Yun Cao, MS, Dean D. Metcalfe, MD, FAAAAI, Paneez Khoury, MD FAAAAI, Bruce S. Bochner, MD FAAAAI, Amy D. Klion, MD
RATIONALE: Siglec-8 is expressed on eosinophils, basophils and mast cells. Antibodies targeting Siglec-8 are in development for the treatment of myeloid disorders, including systemic mastocytosis (SM). Since shedding of soluble Siglec-8 (sSiglec-8) could interfere with the efficacy of anti-Siglec-8 therapy, sSiglec-8 levels were measured in the serum of patients with a variety of myeloid disorders.

METHODS: Subjects with myeloid variant hypereosinophilic syndrome (MHES), D816V KIT+ systemic mastocytosis (SM) and normal controls (ND) were evaluated on clinical protocols to study eosinophilia and SM. Serum sSiglec-8 levels were measured by sandwich ELISA (limits of detection: 0.5/1 (duplicate/singlicate) to 60 ng/mL).

RESULTS: sSiglec-8 levels were detectable in 6/10 ND and 14/19 MHES subjects (9/11 FIP1L1-PDGFRA-positive, 3/3 idiopathic MHES, 2/2 V617F JAK2-positive, 0/2 exon 13 JAK2 mutation-positive and 0/1 PDGFRB mutation-positive). Mean levels did not differ between the MHES and ND groups (GM 1.27 and 1.86 ng/mL, respectively) and did not correlate with AEC. sSiglec-8 levels in the FIP1L1-PDGFRA-positive subjects decreased significantly in response to imatinib (from 2.41 to 0.93; Wilcoxon test, P<0.05, n=8). Surprisingly, sSiglec-8 was undetectable in all 22 subjects with D816V KIT-positive SM, including 4 D816V KIT-positive SM-eo patients with AEC>1900/μL. SM serum did not inhibit detection of recombinant sSiglec-8 in vitro.

CONCLUSIONS: Despite expression of Siglec-8 on mast cells and eosinophils in subjects with SM, sSiglec-8 levels were not measurable in these patients and are unlikely to interfere with the efficacy of anti-Siglec-8 antibodies. Whether the D816V KIT mutation prevents receptor shedding remains to be elucidated.