Turning mirror-image oligonucleotides into drugs: the evolution of Spiegelmer® therapeutics

Abstract

Spiegelmers are synthetic target-binding oligonucleotides built from non-natural l-nucleotides. Like aptamers, Spiegelmers fold into distinct shapes that bind the targets with high affinity and selectivity. Furthermore, the mirror-image configuration confers plasma stability and immunological passivity. Various Spiegelmers against pharmacologically attractive targets were shown to be efficacious in animal models. Three Spiegelmer candidates: emapticap pegol (NOX-E36; anti-CCL2), olaptesed pegol (NOX-A12; anti-CXCL12) and lexaptepid pegol (NOX-H94; anti-hepcidin), underwent regulatory safety studies, demonstrated good safety profiles in healthy volunteers and were taken into Phase IIa studies in patients. Proof-of-concept for emapticap pegol has recently been demonstrated in diabetic nephropathy patients. Furthermore, promising interim Phase IIa data of olaptesed pegol and lexapteptid pegol also suggest efficacy in the respective patient populations.

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

“…NOX-A12 is a so-called Spiegelmer ® , a class of oligonucleotide therapeutics made from the Lstereoisomer acting like a "chemical antibody" with very high stability in biological fluids and no immunogenicity (24). We have now used NOX-A12 to induce a redistribution of BMSCs from the bone marrow to retinal lesions that had been induced by a single dose of sodium iodate (NaIO 3 ) in mice.…”

Increasing Tumor-Infiltrating T Cells through Inhibition of CXCL12 with NOX-A12 Synergizes with PD-1 Blockade

“…NOX-A12 (olaptesed pegol) is an L-configured aptamer (Spiegelmer) (8) that binds CXCL12 with high affinity and specificity across various species, including human, mouse, and rat (9). NOX-A12 was previously shown to not only directly bind and inhibit, but also detach the cell-surface bound CXCL12, leading to abrogation of the CXCL12 gradient (10).…”

New agents in HSC mobilization

“…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.…”

“…An interesting new class of SDF-1 inhibitors is the "aptamer" or "Spiegelmer" family of drugs [42]. 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].…”