Abstract
Imetelstat sodium (GRN163L; hereafter, imetelstat) is a first-in-class telomerase inhibitor that has demonstrated activity in patients with myeloproliferative neoplasms (MPNs). Treatment with imetelstat has been associated with thrombocytopenia and other hematologic adverse effects that were manageable and reversible. Toll-like receptors (TLRs) are proteins that recognize pathogen-associated molecular patterns and stimulate innate immune and pro-apoptotic responses. Because imetelstat is an oligonucleotide, and some oligonucleotides can activate TLRs, we conducted an in vitro study to rule out the possibility of imetelstat-associated thrombocytopenia by off-target effects through activation of TLRs. We used HEK293 cell lines stably co-expressing a human TLR gene and an NFκB-inducible reporter to investigate whether imetelstat can activate TLR signaling. We treated the cells with imetelstat or control oligonucleotides for 20 h, and used absorbance of the culture media to calculate the reporter activity. Treatment with imetelstat within or beyond the clinically relevant concentrations had no stimulatory effect on TLR2, TLR3, TLR4, TLR5, TLR7, or TLR9. This result was not surprising since the structure of imetelstat does not meet the reported minimal structural requirements for TLR9 activation. Furthermore, imetelstat treatment of the MPN cell line HEL did not impact the expression of TLR signaling pathway target genes that are commonly induced by activation of different TLRs, whereas it significantly reduced its target gene hTERT, human telomerase reverse transcriptase, in a dose- and time-dependent manner. Hence, cytopenias, especially thrombocytopenia observed in some patients treated with imetelstat, are not mediated by off-target interactions with TLRs.
Highlights
Imetelstat has demonstrated activity in patients with myeloproliferative neoplasms, including essential thrombocythemia [1]; primary, post-essential thrombocythemia, or post-polycythemia vera myelofibrosis [2,3]; and lower-risk myelodysplastic syndromes [4,5]
Lipopeptides, double-stranded RNA, lipopolysaccharide, and flagellin activate TLR2, TLR3, TLR4, and TLR5, respectively; TLR9 is activated by deoxycytidylate-phosphate-deoxyguanylate DNA [10]
We investigated whether imetelstat activates Toll-like receptors (TLRs) and, by extension, whether the thrombocytopenia observed in some patients treated with imetelstat may be due to the off-target stimulation of these receptors
Summary
Imetelstat has demonstrated activity in patients with myeloproliferative neoplasms, including essential thrombocythemia [1]; primary, post-essential thrombocythemia, or post-polycythemia vera myelofibrosis [2,3]; and lower-risk myelodysplastic syndromes [4,5]. Treatment with various concentrations of imetelstat even at concentrations higher than clinically relevant showed that SEAP reporter activity resulted in no significant difference compared to untreated cell controls, indicating no stimulatory effect on TLR2, TLR3, TLR4, TLR5, TLR7, or TLR9; neither mismatch nor sense oligonucleotides stimulated the TLRs in this study (Figure 1).
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