Pharmacologic Characterization of ALD1910, a Potent Humanized Monoclonal Antibody against the Pituitary Adenylate Cyclase-Activating Peptide
| Autor: | Brian Baker, Dan Scott Allison, Lee Hendrix, David Jurchen, Susan Pederson, Heidi Boshaw, Sam Marzolf, Jens J. Billgren, John A. Latham, Vanessa Lisbeth Rubin, Gayle Kwon, Cristina Moldovan Loomis, Leon F. Garcia-Martinez, Pei Fan, Roger Cady, Erica Stewart, Ethan W. Ojala, Charlie Karasek, Jenny Mulligan, Michelle Scalley-Kim, Lisa Perrino McCulloch, Benjamin H. Dutzar |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine medicine.drug_class Migraine Disorders Population Dose-Response Relationship Immunologic Pharmacology Calcitonin gene-related peptide Antibodies Monoclonal Humanized Monoclonal antibody PC12 Cells Rats Sprague-Dawley Epitopes 03 medical and health sciences 0302 clinical medicine Chronic Migraine Antibody Specificity Animals Humans Medicine education education.field_of_study business.industry Vasoactive intestinal peptide receptor medicine.disease Rats Kinetics Pituitary adenylate cyclase-activating peptide 030104 developmental biology Migraine Calcitonin Pituitary Adenylate Cyclase-Activating Polypeptide Molecular Medicine business 030217 neurology & neurosurgery |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 369:26-36 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.118.253443 |
| Popis: | 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 provided prevention in patients with episodic and chronic migraine. Heterogeneity is present within each diagnosis and patient's response to treatment, suggesting migraine as a final common pathway potentially activated by multiple mechanisms, e.g., not all migraine attacks respond to 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 pituitary adenylate cyclase-activating peptide type I receptor, vasoactive intestinal peptide receptor 1, and vasoactive intestinal peptide receptor 2. ALD1910 recognizes a nonlinear 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. |
| Databáze: | OpenAIRE |
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