Hematopoietic Stem and Progenitor Cell Mobilization in Mice and Humans by a First-in-Class Mirror-Image Oligonucleotide Inhibitor of CXCL12

Abstract

NOX-A12 is a PEGylated mirror-image oligonucleotide (a so-called Spiegelmer) that binds to CXCL12 (stromal cell-derived factor-1, SDF-1) with high affinity thereby inhibiting CXCL12 signaling on both its receptors, CXCR4 and CXCR7. In animals, NOX-A12 mobilized white blood cells (WBCs) and hematopoietic stem and progenitor cells (HSCs) into peripheral blood (PB). In healthy volunteers, single doses of NOX-A12 had a benign safety profile and also dose-dependently mobilized WBCs and HSCs into PB. HSC peak mobilization reached a plateau at five times the baseline level at an i.v. dose of 5.4 mg/kg. In accordance with the plasma half-life of 38 h, the duration of the WBC and HSC mobilization was long lasting and increased dose-dependently to more than 4 days at the highest dose (10.8 mg/kg). In conclusion, NOX-A12 may be appropriate for therapeutic use in and beyond mobilization of HSCs, e.g., in long-lasting mobilization and chemosensitization of hematological cancer cells.

CXCL12/SDF-1-Dependent Retinal Migration of Endogenous Bone Marrow-Derived Stem Cells Improves Visual Function after Pharmacologically Induced Retinal Degeneration

“…NOX-A12 has a benign safety profile and is well tolerated. The mobilizing effect has been induced by a single injection in mice, monkeys and humans as opposed to G-CSF for which several injections are necessary (23).…”

NOX-A12: mobilizing CLL away from home

“…7 A similar efficacy in leukocyte mobilization characterizes NOX-A12 and plerixafor. Nevertheless, NOX-A12 seems to have a more pronounced taste for lymphocytes and to mediate a longerterm mobilization of leukemic cells than plerixafor.…”

New agents in HSC mobilization

“…+ cells that persisted in the blood for up to 4 days at the highest dose tested, which was attributed to its long plasma half-life (~38 h) [45]. The sustained mobilization of CD34 + cells may be desired to allow time for collection via apheresis but also drew speculation to its potential benefits towards chemosensitization of haematological cancers (Table 1) [43,45,46].…”

“…The sustained mobilization of CD34 + cells may be desired to allow time for collection via apheresis but also drew speculation to its potential benefits towards chemosensitization of haematological cancers (Table 1) [43,45,46]. Should NOX-A12 perform favourably in clinical studies, it may open doors for the development of other targetspecific Spiegelmer drugs for HSC mobilization.…”

“…Spiegelmers are a class of artificial mirrorimage RNA oligonucleotide drugs constructed using nonnatural L-ribose units and have been of substantial clinical interest since the age-related macular degeneration aptamer drug Macugen ® (Pfizer) was first approved by the FDA in 2005 (Reviewed in [42,43]. NOX-A12 (olaptesed pegol) is a PEGylated Spiegelmer that specifically targets SDF-1 and has been shown to induce rapid mobilization of murine HSPC either alone or synergistically with G-CSF [44,45]. In human trials, NOX-A12-induced mobilization resulted in significant numbers of human CD34…”