Author: Stephen D Silberstein

Monoclonal antibodies: sites of action

There are four mAbs currently in development; three are humanized mAbs targeting the CGRP ligand and one is a fully human mAb against the CGRP receptor. They have a rapid onset of efficacy (roughly one week) following a single dose administration. All are thought to work peripherally.

Therapeutic mAbs are designed to achieve high target specificity and low systemic adverse effect. CGRP function-blocking mAbs can inhibit neurogenic vasodilatation without affecting heart rate or arterial blood pressure on rats.1 Current CGRP function-blocking mAb targets are either CGRP (the ligand) or the canonical CGRP receptor. All have high target-binding affinity (picomolar range) and low nonspecific binding.2,3

No clinical trial so far has reported significant liver toxicity or drug-antibody interaction, which is to be expected since mAbs are not metabolised primarily by the cytochrome p450 pathway. They are broken down into amino acids by reticuloendothelial cells in skin, muscle, liver, and guts, contributing 33%, 24%, 16%, and 12% of total IgG elimination, respectively.4, 5 The mAbs must be given IV or subcutaneously. In the systemic circulation, mAbs have a long half-life (20-45 days).

The site of action of a mAb is largely determined by its distribution, which is affected by the type of vascular endothelium (continuous, fenestrated, sinusoidal) and the type of transport (receptor-mediated vs. passive, transcellular vs. paracellular). Due to its large size, CGRP function-blocking mAb is impermeable to a healthy blood-brain barrier (BBB), but can cross passively via paracellular extravasation to a BBB-deficient region (e.g. meninges, circumventricular regions) or any ‘leaky’ vascular endothelium.

Tissue distribution of intravenously administered IgG is estimated at 10-15% of plasma concentration in skin, lung, kidney, liver, spleen, and heart, but only 0.35% in brain.4 It is commonly believed that migraine does not disrupt the BBB integrity. Schankin et al showed no breakdown of the BBB during an NO-induced migraine.6 However, cortical spreading depression can induce increased pinocytosis even with intact tight junction, suggestive for a transcellular mechanism;7 its clinical significance remains unknown.

Brain-nerve barrier, despite having no astrocyte support, is now regarded as ‘tight’ as BBB.8, 9 In sensory ganglia such as the trigeminal ganglion (TG), fenestrated capillaries exist, allowing mAb to extravasate.10 Knyazeva et al found IgG extravasated in the perivascular tissue of studied ganglia, including the caudal vagus, cervical, ciliary, otic, and sphenopalatine ganglia, except myenteric ganglia (TG not studied).

Interganglionic differences in macromolecule transport exist. The caudal ganglion of the vagus is highly permeable, whereas, the myenteric plexus is almost impermeable.11 Johnson et al examined the distribution of a CGRP mAb LY2951742; the rank order of tissue levels was dura mater = spleen > TG >> hypothalamus = spinal cord = prefrontal cortex = cerebellum = CSF. The LY2951742 peripheral tissue levels (dura, spleen, TG) were 4-11% of plasma levels; the CNS tissue levels were <0.4% of plasma levels.12 For CGRP receptor mAb, it may even actively accumulate at the target site from its receptor binding. TG clearly is the key target of interest.

Other autonomic/sensory ganglia also play certain roles in migraine, but their involvement upon CGRP blockade have not been clarified yet. Non-target distribution (liver, spleen, skin, endocrine glands, circulation, etc) is not trivial, but so far no major cardiac, pulmonary, gastric, or hepatic adverse event has been reported.13-17 Pertinent to migraine, CGRP function-blocking mAbs likely take action outside the BBB in meninges and circumventricular regions, as well as neural ganglia and trigeminovascular system. This expectedly influences CGRP’s action on neurons and immune cells (e.g. MCs, SGCs) inhibiting vasodilatation, neurogenic inflammation, and pain sensitisation.

Dr Stephen D Silberstein MD
Professor of Neurology and Director, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, Pennsylvania

References

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