(Abstract release date: Sep 23, 2015) ECTRIMS Online Library. Mueller B. Oct 8, 2015; 115435
Summary: Repulsive Guidance Molecule a (RGMa) is a potent inhibitor of axon regeneration and remyelination and is involved in neuronal cell death. In addition RGMa plays an important role in neuroinflammation. Targeting RGMa by the selective antibody ABT-555 promotes axon regeneration, enhances neuroprotection, stimulates remyelination and decreases microglial inflammation.
Objective: To present the preclinical data of ABT-555 in several different MS-related animal models.
Methods: Anti-RGMa antibodies, including ABT-555, were evaluated in a rat spinal cord targeted experimental autoimmune encephalitis (tEAE) model induced by myelin oligodendrocyte glycoprotein (MOG)-sensitization followed by local injection of tumor necrosis factor-beta (TNF)-b and gamma interferon (IFN)-g; in an optic neuritis model using the same protocol of MOG sensitization; and in a mouse MOG disseminated EAE model (dEAE) immunized with MOG in complete Freund´s adjuvant and boosted with pertussis toxin.
Results: Administration of ABT-555 accelerated functional recovery in both EAE models, enhanced axonal regeneration within inflammatory lesions, and stimulated remyelination. Treatment with RGMa antibodies also decreased the inflammatory signal by CD68+ cells within the spinal cord. ABT-555 stimulated regenerative axon growth within the inflammatory optic nerve lesion in a dose dependent manner on immunohistochemistry (IHC) and reduced degeneration of the retinal nerve fiber layer measured using optical coherence tomography (OCT), proving its potent neuroprotective efficacy .
Conclusions: The specific targeting of RGMa by ABT-555 in several animal models of autoimmune inflammatory disease of the CNS resulted in immune modulation and neuroprotection and neuroregeneration and this new therapeutic strategy may provide novel benefit in patients with MS and warrants further study. The early clinical evaluation of ABT-555 in healthy volunteers and MS patients is currently underway.
Disclosure: All authors are employees of AbbVie. The design, study conduct, and financial support for this research was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.