The anti-CGRP mAb Fremanezumab reverts the anti-inflammatory effects of CGRP in vitro but does not alter disease evolution in a mouse model of progressive multiple sclerosis

Migraine has been reported to be twice as prevalent in patients with multiple sclerosis (MS) compared to the non-MS population, highlighting the importance of the treatment for migraine in the MS population. Because of their efficacy, safety profile, and target specificity, the anti-CGRP monoclonal antibodies (mAbs) represent a promising option in MS patients concomitantly exposed to disease-modifying drugs. However, growing evidence reports the role of CGRP in regulating the immune system, raising a question about the safety use of anti-CGRP mAbs in autoimmune disorders such as MS. In the present study, by adopting NOD mice immunized with MOG35-55 as a model of progressive experimental autoimmune encephalomyelitis (PEAE), we evaluated the effects of the anti-CGRP mAb fremanezumab on disease evolution. We report that CGRP inhibited both LPS-induced microglia activation and lymphocyte proliferation in a concentration-dependent manner and that a concomitant fremanezumab exposure counteracted these effects in vitro. However, we found that fremanezumab administered every 2 weeks from the day of immunization, did not worsen disease evolution or survival in PEAE mice. Accordingly, no difference in innate and adaptive immune responses as well as spinal cord degeneration was observed in immunized mice treated with fremanezumab. Notably, we also demonstrated the ability of fremanezumab to reach the site of neurodegeneration, showing its presence in the spinal cord. Data indicate that CGRP has an irrelevant immunosuppressant effect in the complex pathophysiological scenario of MS, and suggest that the use of anti-CGRP antibodies for migraine treatment in MS patients is safe.