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Papers of the Week

Papers: 12 Jan 2019 - 18 Jan 2019

Animal Studies, Pharmacology/Drug Development


2019 Apr

J Pharmacol Exp Ther



Pharmacologic Characterization of ALD1910, a Potent Humanized Monoclonal Antibody against the Pituitary Adenylate Cyclase Activating Peptide.


Moldovan Loomis C, Dutzar B, Ojala EW, Hendrix L, Karasek C, Scalley-Kim M, Mulligan J, Fan P, Billgren J, Rubin V, Boshaw H, Kwon G, Marzolf S, Stewart E, Jurchen D, Pederson SM, Perrino McCulloch L, Baker B, Cady RK, Latham JA, et al.
J Pharmacol Exp Ther. 2019 Apr; 369(1):26-36.
PMID: 30643015.


Migraine is a debilitating disease that affects almost 15% of the population worldwide and is the first cause of disability in people under 50 years of age, yet its etiology and pathophysiology remain incompletely understood. Recently, small molecules and therapeutic antibodies that block the calcitonin gene-related peptide (CGRP) signaling pathway have reduced migraine occurrence and aborted acute attacks of migraine in clinical trials and provide prevention in patiens with episodic and chronic migraine. Heterogeneity is present within each diagnosis and a patient's response to treatment, suggesting migraine as a final common pathway potentially activated by multiple mechanisms, e.g. not all migraine attacks respond or are prevented by anti-CGRP pharmacological interventions. Consequently, other unique mechanisms central to migraine pathogenesis may present new targets for drug development. Pituitary adenylate cyclase-activating peptide (PACAP) is an attractive novel target for treatment of migraines. We generated a specific, high affinity, neutralizing monoclonal antibody (ALD1910) with reactivity to both PACAP38 and PACAP27. In vitro, ALD1910 effectively antagonizes PACAP38 signaling through the PAC1-R, VPAC1-R, and VPAC2-R. ALD1910 recognizes a non-linear epitope within PACAP and blocks its binding to the cell surface. To test ALD1910 antagonistic properties directed against endogenous PACAP, we developed an umbellulone-induced rat model of neurogenic vasodilation and parasympathetic lacrimation. In vivo, this model demonstrates that the antagonistic activity of ALD1910 is dose-dependent, retaining efficacy at doses as low as 0.3 mg/kg. These results indicate that ALD1910 represents a potential therapeutic antibody to address PACAP-mediated migraine.