Tuesday, 27 October 2015

Another LINGO in the making or will it be a NOGO? Anti-repulsive guidance molecule for regeneration

ABT-555, a human anti-RGMa monoclonal antibody promotes axon regeneration and neuroprotection in multiple sclerosis models
(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.


Repulsive guidance molecule isoform a (RGMa) is another repulsive/inhibitory cue for axonal elongation. Theoretically, by blocking the activity of RGMa you can do the opposite, which is promote axonal elongation. The authors demonstrate that an antibody to RGMa (ABT-555) can stimulate regeneration within MS-like lesions in mice spinal cord and in optic neuritis. In the optic neuritis model they demonstrate that compared to the control eye which did not receive treatment, the ABT-555 treated eyes had up to 30% regenerative growth.

You would imagine AbbVie would like to get this into a clinical trial? And this may be their intention. But I would say there has been a deluge of these therapeutics now in the regenerative field, not excluding LINGO-1 in MS, and may not be the panacea they are purported to be. Moreover, there is a reason why humans and other organisms express these molecules in normal circumstances, since they play a prominent role in the topographical architecture of central nervous system during development. By blocking them, is there a chance that we would also mess up the design of our central nervous system, which any sensible neuroscientist will not deny is plastic?!

3 comments:

  1. Dear NDG,

    Do we know what the trial design would be for anti lingo 1 type drugs? I understand why DMT trials take a long time but would this classification need similar length of trials?

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  2. It would depend on the trial group tested. A focal model such as optic neuritis is pretty straightforward and can be a placebo controlled trial lasting 6 months with optical coherence tomography which measures the retinal nerve fibre layer thickness as the primary outcome. If you start getting into RRMS and SPMS the minimum trial period is two years. This is based on the sensitivity of the outcome measure which is MRI. If you're looking for clinical benefit the trial will have to be much longer. As these are purported to be regenerative the outcome measure of time to disability progression used in neuroprotection trials which allow for a shorter trial doesn't answer the primary question! The newer MRI measures such as MTR, NODDI may allow you to use MRI as the outcome over a two year period.

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