CGRP function‐blocking antibodies inhibit neurogenic vasodilatation without affecting heart rate or arterial blood pressure in the rat

Abstract

Background and purpose: Calcitonin gene-related peptide (CGRP) receptor antagonists effectively abort migraine headache and inhibit neurogenic vasodilatation in humans as well as rat models. Monoclonal antibodies typically have long half-lives, and we investigated whether or not function-blocking CGRP antibodies would inhibit neurogenic vasodilatation with a long duration of action and therefore be a possible approach to preventive therapy of migraine. During chronic treatment with anti-CGRP antibodies, we measured cardiovascular function, which might be a safety concern of CGRP inhibition. Experimental approach: We used two rat blood flow models that measure electrically stimulated vasodilatation in the skin or in the middle meningeal artery (MMA). These vasomotor responses are largely dependent on the neurogenic release of CGRP from sensory afferents. To assess cardiovascular function during chronic systemic anti-CGRP antibody treatment, we measured heart rate and blood pressure in conscious rats. Key results: Treatment with anti-CGRP antibodies inhibited skin vasodilatation or the increase in MMA diameter to a similar magnitude as treatment with CGRP receptor antagonists. Although CGRP antibody treatment had a slower onset of action than the CGRP receptor antagonists, the inhibition was still evident 1 week after dosing. Chronic treatment with anti-CGRP antibodies had no detectable effects on heart rate or blood pressure. Conclusions and implications:We showed for the first time that anti-CGRP antibodies exert a long lasting inhibition of neurogenic vasodilatation in two different rat models of arterial blood flow. We have provided strong preclinical evidence that anti-CGRP antibody may be a suitable drug candidate for the preventive treatment of migraine.

Targeting CGRP: A New Era for Migraine Treatment

“…CGRP antibodies inhibited skin vasodilatation in rats, still evident 1 week after dosing. No effects on animal heart rate or blood pressure were detected; this is consistent with CGRP primarily being a compensatory peptide with modulatory roles in the body [34,99]. Side effects from a broad range of dosages (0.2-2000 mg) of intravenous LBR-101 were reported to be mostly mild, with one serious adverse event of 'thoracic aortic aneurysm' in a participant who was later diagnosed with Ehlers-Danlos syndrome.…”

Complementary Use of Label-Free Real-Time Biosensors in Drug Discovery of Monoclonal Antibodies

“…4C and 4D), but they agreed closely with those obtained for similar analyses on ProteOn and Biacore platforms (Fig. 5) and previously published values (Zeller et al, 2008). The Octet and ProteOn data were performed in a parallel "one-shot" kinetic mode whereas the Biacore data were collected in a serial multi-cycle mode by regenerating the surfaces after each injection.…”

Anti-CGRP monoclonal antibodies in migraine: current perspectives

“…As already reported, however, preclinical studies in monkeys and rats demonstrate that anti-CGRP mAbs, administered in a way to determine a long-term inhibition of CGRP, do not cause significant electrocardiogram or hemodynamic changes [12,85,87,93] and their administration in humans-both healthy subjects and patients-at wide ranges of dosage does not produce relevant cardiovascular side effects or laboratory abnormalities [86]. No other off-target impairment, such as the liver toxicity observed with GCRP antagonists, has so far been recorded.…”