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

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.

ALD1613, a Novel Long-Acting Monoclonal Antibody to Control ACTH-Driven Pharmacology.

Adrenocorticotropic hormone (ACTH) is the primary regulator of adrenal glucocorticoid production. Elevated levels of ACTH play a critical role in disease progression in several indications, including congenital adrenal hyperplasia and Cushing disease. We have generated a specific, high-affinity, neutralizing monoclonal antibody (ALD1613) to ACTH. In vitro, ALD1613 neutralizes ACTH-induced signaling via all 5 melanocortin receptors and inhibited ACTH-induced cyclic adenosine monophosphate accumulation in a mouse adrenal cell line (Y1). ALD1613 administration to wild-type rats significantly reduced plasma corticosterone levels in a dose-dependent manner. In rodent models with either chronic infusion of ACTH or acute restraint stress-induced ACTH, corticosterone levels were significantly reduced by ALD1613. Administration of ALD1613 to nonhuman primates on days 1 and 7 stably reduced plasma cortisol levels >50% for 57 days. ALD1613 demonstrates the potential of a monoclonal antibody to be an effective therapeutic for conditions with elevated ACTH levels.