Soluble Siglec-8 Levels Are Detectable In Subjects With Myeloid Variant Hypereosinophilic Syndromes, But Not In Those With D816V KIT+ Systemic Mastocytosis

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.