Assessment of Opicinumab in Acute Optic Neuritis Using Multifocal Visual Evoked Potential

Klistorner, Alexander; Chai, Yi; Leocani, Letizia; Xu, Lei; Cadavid, Diego; Butzkueven, Helmut; Garrick, R.; Vanopdenbosch, Ludo; Frederiksen, Jette; Aktaş, Orhan; Albrecht, Philipp; Ziemssen, Focke; Ziemssen, Tjalf; Comi, Giancarlo; Dalmau, Bernardo Sánchez; Andersson, Magnus; Plant, Gordon T.; Matthews, Tim; Williams, G.

doi:10.1007/s40263-018-0575-8

Cited by 41 publications

(59 citation statements)

References 37 publications

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“…In a substudy of a recent clinical trial assessing the monoclonal anti-LINGO-1 antibody opicinumab in acute ON, fellow eyes of placebotreated, but not opicinumab-treated, patients showed progressive multifocal visual evoked potential (VEP) amplitude loss over 8 months. 34 Similarly, Raz et al 16 found changes to the latency of late peaks of the VEP of NON eyes, which were not attributable to demyelination; the authors attributed these changes to an adaptive mechanism to maximize preservation of stereopsis in their patients with unilateral ON. We are unable to reach firm conclusions as to the etiology of our INL thickness changes, but we suggest subclinical inflammation of the fellow eye as a potential candidate.…”

Section: Discussionmentioning

confidence: 96%

Bilateral retinal pathology following a first-ever clinical episode of autoimmune optic neuritis

Wicki

Manogaran

Simić

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveThis longitudinal study aimed to assess changes in retinal structure and visual function following a first-ever episode of acute optic neuritis (ON).MethodsClinical and optical coherence tomography (OCT) data obtained over a period of 12 months were retrospectively analyzed in 41 patients with a first-ever clinical episode of acute ON. OCT scans, high-contrast visual acuity (HCVA), and low-contrast visual acuity (LCVA) were acquired at baseline and at 1, 3, 6, and 12 months thereafter. Macular ganglion cell and inner plexiform layer (GCIP), peripapillary retinal nerve fiber layer (pRNFL), and macular inner nuclear layer (INL) thicknesses were assessed by OCT. Linear mixed-effects models were used to analyze OCT variables of ipsilateral ON and contralateral non-ON (NON) eyes over time.ResultsThe mean change of GCIP thickness in ON eyes was significant at all follow-up time points, with nearly 75% of the total reduction having occurred by month 1. In ON eyes, thinner GCIP thickness at month 1 correlated with lower LCVA at month 3. Mean pRNFL thickness in ON eyes differed significantly from NON eyes at all postbaseline time points. INL thickness was significantly increased in ON eyes (month 1) but also in contralateral NON eyes (month 12).ConclusionsRetinal structural damage develops rapidly following acute ON and is associated with subsequent functional visual deficits. Our results also suggest bilateral retinal pathology following unilateral ON, possibly caused by subclinical involvement of the contralateral NON eyes. Moreover, our data may assist in clinical trial planning in studies targeting tissue damage in acute ON.

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Section: Discussionmentioning

confidence: 96%

Bilateral retinal pathology following a first-ever clinical episode of autoimmune optic neuritis

Wicki

Manogaran

Simić

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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“…Although slightly more time consuming, the latency results of mfVEP are more meaningful and reliable, which results in significantly smaller sample size needed to demonstrate remyelination. 37 Although we did not perform mfVEP in control subjects (which may be considered as another limitation), the conclusions were mainly drawn from intrasubject analysis between ON and NON in patients with MS.…”

Section: Discussionmentioning

confidence: 98%

Chronic demyelination exacerbates neuroaxonal loss in patients with MS with unilateral optic neuritis

You¹,

Barnett²,

Yiannikas

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo examine the effect of chronic demyelination in the optic nerve of patients with MS on progressive loss of retinal ganglion cell (RGC) axons.MethodsProgressive retinal nerve fiber layer (RNFL) loss, as measured by optical coherence tomography, was longitudinally examined in 51 patients with MS with a history of unilateral optic neuritis (ON) and 25 normal controls. Patients were examined annually with a median of 4-year follow-up. Pairwise intereye comparison was performed between ON and fellow non-ON (NON) eyes of patients with MS using the linear mixed-effects model and survival analysis. The latency asymmetry of multifocal visual evoked potential (mfVEP) was used to determine the level of demyelination in the optic nerve.ResultsAlthough both ON and NON eyes demonstrate significantly faster loss of RGC axons compared with normal subjects, ON eyes with severe chronic demyelination show accelerated thinning in the RNFL in the temporal sector of the optic disc (temporal RNFL [tRNFL]) compared with fellow eyes (evidenced by both the linear mixed-effects model and survival analysis). Furthermore, progressive tRNFL thinning is associated with the degree of optic nerve demyelination and reflects the topography of pathology in the optic nerve. More rapid axonal loss in ON eyes is also functionally evidenced by mfVEP amplitude reduction, which correlates with the level of optic nerve demyelination.ConclusionsAlthough the effect of demyelination on axonal survival has been demonstrated in experimental studies, our results provide first clinically meaningful evidence that chronic demyelination is associated with progressive axonal loss in human MS.

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“…The study showed a trend toward improvement in the affected eye and significant improvement in the fellow eye. 22 However, there is a lack of qualified methods to directly assess CNS remyelination in humans.…”

Section: Discussionmentioning

confidence: 99%

“…12,20 It is currently being investigated in clinical trials as a potential treatment to repair neuronal damage that occurs in the CNS of individuals with multiple sclerosis (MS) (AFFINITY: clinical trial.gov number NCT03222973). 3,21,22 To investigate the mechanism of action of the Li81 antibody, we solved the crystal structure of the LINGO-1 ectodomain/Li81 Fab complex. 20 An unexpected feature of the structure was that the Li81 Fab contained two binding sites for LINGO-1, and this led to the formation of a heterotetrameric unit that contained 2 copies each of the Fab and LINGO-1, where the classical primary binding of the Fab through its complementarity-determining regions (CDRs) to LINGO-1 created a secondary binding site that recruited a second copy of LINGO-1 (Figure 1(b) vs. Figure 1 (a)).…”

Section: Introductionmentioning

confidence: 99%

Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site

Hanf

Arndt

Liu

et al. 2020

mAbs

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2020) Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site, mAbs, 12:1, 1713648, ABSTRACT LINGO-1 is a membrane protein of the central nervous system (CNS) that suppresses myelination of axons. Preclinical studies have revealed that blockade of LINGO-1 function leads to CNS repair in demyelinating animal models. The anti-LINGO-1 antibody Li81 (opicinumab), which blocks LINGO-1 function and shows robust remyelinating activity in animal models, is currently being investigated in a Phase 2 clinical trial as a potential treatment for individuals with relapsing forms of multiple sclerosis (AFFINITY: clinical trial.gov number NCT03222973). Li81 has the unusual feature that it contains two LINGO-1 binding sites: a classical site utilizing its complementarity-determining regions and a cryptic secondary site involving Li81 light chain framework residues that recruits a second LINGO-1 molecule only after engagement of the primary binding site. Concurrent binding at both sites leads to formation of a 2:2 complex of LINGO-1 with the Li81 antigen-binding fragment, and higher order complexes with intact Li81 antibody. To elucidate the role of the secondary binding site, we designed a series of Li81 variant constructs that eliminate it while retaining the classic site contacts. These Li81 mutants retained the high affinity binding to LINGO-1, but lost the antibody-induced oligodendrocyte progenitor cell (OPC) differentiation activity and myelination activity in OPC-dorsal root ganglion neuron cocultures seen with Li81. The mutations also attenuate antibody-induced internalization of LINGO-1 on cultured cortical neurons, OPCs, and cells over-expressing LINGO-1. Together these studies reveal that engagement at both LINGO-1 binding sites of Li81 is critical for robust functional activity of the antibody. ARTICLE HISTORY

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Assessment of Opicinumab in Acute Optic Neuritis Using Multifocal Visual Evoked Potential

Cited by 41 publications

References 37 publications

Bilateral retinal pathology following a first-ever clinical episode of autoimmune optic neuritis

Bilateral retinal pathology following a first-ever clinical episode of autoimmune optic neuritis

Chronic demyelination exacerbates neuroaxonal loss in patients with MS with unilateral optic neuritis

Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site

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