Establishment of monoclonal antibodies against the extracellular domain that block binding of NMO-IgG to AQP4

Miyazaki, Kunihiko; Abe, Yoichiro; Iwanari, Hiroko; Suzuki, Yasunosuke; Kikuchi, Takahiro; Ito, Takashi; Kato, Jungo; Kusano-Arai, Osamu; Takahashi, Toshiyuki; Nishiyama, Shuhei; Ikeshima-Kataoka, Hiroko; Tsuji, Shoji; Arimitsu, Takeshi; Kato, Yasuhiro; Sakihama, Toshiko; Toyama, Yoshiaki; Fujihara, Kazuo; Hamakubo, Takao; Yasui, Masato

doi:10.1016/j.jneuroim.2013.03.003

Cited by 32 publications

(42 citation statements)

References 29 publications

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“…This event is, in turn, due to the higher propensity of the side chain of the mutated residue at position 69 to attract the side chain of T56. As mentioned above, our herein presented hypothesis is supported by experimental literature [25,52]. In particular Miyazaki et al [52] conclude not only that the "replacement of loop A drastically reduces the binding of the antibodies to human AQP4" but also that, among the other residues, "T62 and/or L64 are involved in the epitope of the monoclonal antibodies".…”

Section: Discussionsupporting

confidence: 82%

“…As mentioned above, our herein presented hypothesis is supported by experimental literature [25,52]. In particular Miyazaki et al [52] conclude not only that the "replacement of loop A drastically reduces the binding of the antibodies to human AQP4" but also that, among the other residues, "T62 and/or L64 are involved in the epitope of the monoclonal antibodies". The epitope molecular features are recognition elements essential to address the design of modulators of the NMO-IgG AQP4 binding.…”

Section: Discussionsupporting

confidence: 82%

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Challenging AQP4 druggability for NMO-IgG antibody binding using molecular dynamics and molecular interaction fields

Mangiatordi

Alberga

Siragusa

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Neuromyelitis optica (NMO) is a multiple sclerosis-like immunopathology disease affecting optic nerves and the spinal cord. Its pathological hallmark is the deposition of a typical immunoglobulin, called NMO-IgG, against the water channel Aquaporin-4 (AQP4). Preventing NMO-IgG binding would represent a valuable molecular strategy for a focused NMO therapy. The recent observation that aspartate in position 69 (D69) is determinant for the formation of NMO-IgG epitopes prompted us to carry out intensive Molecular Dynamics (MD) studies on a number of single-point AQP4 mutants. Here, we report a domino effect originating from the point mutation at position 69: we find that the side chain of T62 is reoriented far from its expected position leaning on the lumen of the pore. More importantly, the strength of the H-bond interaction between L53 and T56, at the basis of the loop A, is substantially weakened. These events represent important pieces of a clear-cut mechanistic rationale behind the failure of the NMO-IgG binding, while the water channel function as well as the propensity to aggregate into OAPs remains unaltered. The molecular interaction fields (MIF)-based analysis of cavities complemented MD findings indicating a putative binding site comprising the same residues determining epitope reorganization. In this respect, docking studies unveiled an intriguing perspective to address the future design of small drug-like compounds against NMO. In agreement with recent experimental observations, the present study is the first computational attempt to elucidate NMO-IgG binding at the molecular level, as well as a first effort toward a less elusive AQP4 druggability.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 82%

Challenging AQP4 druggability for NMO-IgG antibody binding using molecular dynamics and molecular interaction fields

Mangiatordi

Alberga

Siragusa

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…Such trends are observed also when the two computed C-alpha distances (monomer A vs. B and monomer C vs. D) are considered separately. Taken together, these observations support the key role of T62 as representative of the loop A conformation, in agreement with prior studies [29,30,50]. …”

Section: Resultssupporting

confidence: 93%

Comparative molecular dynamics study of neuromyelitis optica-immunoglobulin G binding to aquaporin-4 extracellular domains

Alberga

Trisciuzzi

Lattanzi

et al. 2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system in which most patients have serum autoantibodies (called NMO-IgG) that bind to astrocyte water channel aquaporin-4 (AQP4). A potential therapeutic strategy in NMO is to block the interaction of NMO-IgG with AQP4. Building on recent observation that some single-point and compound mutations of the AQP4 extracellular loop C prevent NMO-IgG binding, we carried out comparative Molecular Dynamics (MD) investigations on three AQP4 mutants, TP137-138AA, N153Q and V150G, whose 295-ns long trajectories were compared to that of wild type human AQP4. A robust conclusion of our modeling is that loop C mutations affect the conformation of neighboring extracellular loop A, thereby interfering with NMO-IgG binding. Analysis of individual mutations suggested specific hydrogen bonding and other molecular interactions involved in AQP4-IgG binding to AQP4.

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“…Both small molecule and antibody blocking therapies may be used for disease prevention or during disease exacerbations. To date, no blocking therapy or engineered AQP4 antibody has been shown to disrupt AQP4 water channel function (41,119). Therefore, it is less likely that blocking therapies will disrupt the normal function of AQP4 and produce undesirable toxicity.…”

Section: Neuromyelitis Optica Therapymentioning

confidence: 99%

The Treatment of Neuromyelitis Optica

Kowarik¹,

Soltys²,

Bennett³

2014

Journal of Neuro-Ophthalmology

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Neuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system directed against astrocytes. Initially diagnosed in individuals with monophasic or relapsing optic neuritis and transverse myelitis, NMO is now recognized as a demyelinating disorder with pleiotropic presentations due to the identification of a specific autoantibody response against the astrocyte water channel aquaporin-4 in the majority of individuals. As visual impairment and neurologic dysfunction in NMO are commonly severe, aggressive treatment of relapses and prophylactic immunomodulatory therapy are the focus of treatment. Although there are no approved treatments for NMO, medications and therapeutic interventions for acute and chronic treatment have been the subject of retrospective study and case reports. The goal of this review is to familiarize the reader with biologic and clinical data supporting current treatments in NMO and highlight future strategies based on advancements in our understanding of NMO pathogenesis.

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Establishment of monoclonal antibodies against the extracellular domain that block binding of NMO-IgG to AQP4

Cited by 32 publications

References 29 publications

Challenging AQP4 druggability for NMO-IgG antibody binding using molecular dynamics and molecular interaction fields

Challenging AQP4 druggability for NMO-IgG antibody binding using molecular dynamics and molecular interaction fields

Comparative molecular dynamics study of neuromyelitis optica-immunoglobulin G binding to aquaporin-4 extracellular domains

The Treatment of Neuromyelitis Optica

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