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  • Specific Dissolution of Transthyretin (TTR) Amyloid Deposits in the Ligamentum Flavum of Patients with Lumbar Spinal Stenosis (LSS) by a Human Catalytic Antibody (catabody)

    Final Number:
    204

    Authors:
    Saint-Aaron Morris MD; Stephanie Planque Ph.D.; Michele Marie Johnson MD; Paul Sudhir

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Section on Disorders of the Spine and Peripheral Nerves 2016 Annual Meeting

    Introduction: No pharmacological agent is available to treat the causes of LSS, often necessitating surgical intervention. Thickening of the ligamentum flavum (LF) due to TTR amyloid deposits is thought to frequently occur in LSS (1,2). We reported the degradation of amyloid prepared from purified human TTR in the test-tube (synthetic TTR amyloid) by polyclonal IgM class catabodies, suggesting the catalytic function as a putative first-line defense against age-associated amyloidosis (3). Here we describe a rapid and specific monoclonal catabody for removing TTR amyloid from the LF.

    Methods: Monoclonal catabody secreting cell lines were obtained by flow cytometry of human B cells labeled with an electrophilic TTR amyloid analog (E-TTR) that selectively binds IgM+ catalytic B cells (3). Catalytic degradation and dissolution of synthetic TTR amyloid was measured by radioassay and turbidity assays, respectively. LF was obtained at surgery from patients with LSS. Stenosis was measured by magnetic resonance imaging. Exclusion criteria were lumbar synovial cysts, absence of LF thickening, and age <55. LF tissue sections were treated with catabodies or controls then underwent immunohistochemical TTR amyloid quantification using a TTR amyloid-specific monoclonal IgG (4).

    Results: Synthetic TTR amyloid was rapidly degraded and dissolved by a human IgM catabody devoid of reactivity with physiological TTR or nonspecific protein targets. LF sections from 5 of 6 LSS patients contained abundant TTR amyloid deposits varying over a 25-fold range. The 6th LSS patient expressed LF TTR amyloid at levels comparable to 2 control patients with lumbar synovial cysts. TTR amyloid in LF sections from LSS patients was completely removed by low concentrations of the catabody but not a control IgM.

    Conclusions: TTR amyloid deposition may worsen LSS by increasing ligamentum flavum volume. Catabody clearance of LF TTR deposition opens the route to catabody development as a novel therapeutic option for LSS.

    Patient Care: This research generates more understanding of contributing factors to lumbar stenosis, as well as addresses the potential therapeautic utility of catalytic antibodies for amyloid deposition diseases.

    Learning Objectives: By the conclusion of this session, participants should be able to: (a) recognize TTR amyloid as a contributing factor in LSS; (b)understand the potential of catalytic antibody mediated removal of TTR amyloid as a future treatment option for LSS.

    References: 1. Westermark P, Westermark GT, Suhr OB, Berg S. Transthyretin-derived amyloidosis: probably a common cause of lumbar spinal stenosis. Ups J Med Sci. 2014;119(3):223-8. 2. Yanagisawa A, Ueda M, Sueyoshi T, et al. Mod Pathol. Amyloid deposits derive from transthyretin in the ligamentum flavum as related to to lumbar spinal canal stenosis. 2015;28(2):201-7. 3. Planque SA, Nishiyama Y, Hara M, Sonoda S, Murphy SK, Watanabe K, Mitsuda Y, Brown EL, Massey RJ, Primmer SR, O'Nuallain B, Paul S. Physiological IgM class catalytic antibodies selective for transthyretin amyloid. J Biol Chem. 2014;289(19):13243-58. 4. Phay M, Blinder V, Macy S, Greene MJ, Wooliver DC, Liu W, Planas A, Walsh DM, Connors LH, Primmer SR, Planque SA, Paul S, O'Nuallain B. Transthyretin aggregate-specific antibodies recognize cryptic epitopes on patient-derived amyloid fibrils. Rejuvenation Res. 2014;17(2):97-104.

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