Aptamers Targeting IL17A and Its Receptor Suppress IL17 Signaling in Different Cell Types

Area of Science:

• Biochemistry
• Immunology
• Rheumatology

Background:

• Interleukin-17A (IL-17A) is a critical cytokine in autoimmune arthropathies.
• Current IL-17A inhibitors (monoclonal antibodies) have limitations like immunogenicity and loss of response.

Purpose of the Study:

• To evaluate oligonucleotide aptamers as potential alternatives to monoclonal antibodies for inhibiting IL-17A-driven inflammation.
• To assess aptamer efficacy in cell models relevant to immunoinflammatory rheumatic diseases.

Main Methods:

• Tested 2'-F-RNA aptamers (Apt21-2, Apt3-4) against IL-17A and a DNA aptamer (RA10-6) against the IL-17 receptor.
• Assessed IL-17A functional activity inhibition in PBMCs and patient-derived fibroblast-like synoviocytes (FLSs) from axial spondyloarthritis (axSpA) and rheumatoid arthritis (RA) patients.
• Measured IL-6 and MMP-13 secretion using ELISA and flow cytometry, with secukinumab as a control.

Main Results:

• Aptamers suppressed IL-17A-stimulated IL-6 secretion and proliferation in PBMCs (65-85% efficacy), comparable to secukinumab.
• In axSpA FLS, aptamers showed time-dependent efficacy; RA10-6 maintained high efficacy longer than Apt21-2 and Apt3-4.
• Combined aptamer therapy showed synergistic IL-6 suppression; all aptamers reduced MMP-13 to basal levels. RA FLS exhibited reduced responses.

Conclusions:

• Aptamers exhibit high specificity and sustained efficacy in inhibiting IL-17A signaling in vitro, outperforming antibodies in some aspects.
• Differential efficacy in RA FLS highlights disease heterogeneity, aligning with clinical observations of anti-IL-17 therapies in RA.
• Studied aptamers hold significant potential as novel therapeutic agents for IL-17-associated inflammatory arthropathies, especially spondyloarthritis.