Abstract
We developed a nanotechnology based-cell mediated drug delivery system by loading myelin antigen-specific T cells with nanoparticles bound to anti-CD20 monoclonal antibody. Anti-CD20 antibody is a current treatment (ocrelizumab) for multiple sclerosis (MS), a chronic, inflammatory and autoimmune disease of the central nervous system (CNS). CD20-depletion has been associated with efficacy in active relapsing and progressive MS, but may not efficiently target inflammatory cells compartmentalized in the CNS. In our work, the intravenous transfer of T cells containing nanoparticle-anti-CD20 complex in mice causes B cell depletion in the spleen and in the brain, whereas the injection of anti-CD20 alone depletes B cells only in the spleen. Testing this system in Experimental Autoimmune Encephalomyelitis (EAE), animal model of MS, we found that spinal cord B cell depletion ameliorates the disease course and pathology.
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References
Baldi G, Ravagli C, Franchini MC, D’elios MM, Benagiano M, Bitossi M (2015) Magnetic nanoparticles functionalized with cathecol, production and use thereof [internet]. Available from: https://patents.google.com/patent/WO2015104664A1/en
Ballerini C, Baldi G, Aldinucci A, Maggi P (2015) Nanomaterial applications in multiple sclerosis inflamed brain. J NeuroImmune Pharmacol 10(1):1–13
Batrakova EV, Kabanov AV (2013) Cell-mediated drug delivery to the brain. J Drug Deliv Sci Tech 23(5):419–433
Batrakova EV, Gendelman HE, Kabanov AV (2011) Cell-mediated drug delivery. Expert Opin Drug Deliv 8(4):415–433
Bennett J, Basivireddy J, Kollar A, Biron KE, Reickmann P, Jefferies WA, McQuaid S (2010) Blood-brain barrier disruption and enhanced vascular permeability in the multiple sclerosis model EAE. J Neuroimmunol 229(1–2):180–191
Boross P, Leusen JHW (2012) Mechanisms of action of CD20 antibodies. Am J Cancer Res 2(6):676–690
D’Elios MM, Aldinucci A, Amoriello R et al (2018) Myelin-specific T cells carry and release magnetite PGLA–PEG COOH nanoparticles in the mouse central nervous system. RSC Adv 8(2):904–913
Dong X (2018) Current strategies for brain drug delivery. Theranostics. 8(6):1481–1493
Giuliani F, Fu SA, Metz LM, Yong VW (2005) Effective combination of minocycline and interferon-β in a model of multiple sclerosis. J Neuroimmunol 165(1):83–91
Glennie MJ, French RR, Cragg MS, Taylor RP (2007) Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol 44(16):3823–3837
Goyal K, Koul V, Singh Y, Anand A (2014) Targeted drug delivery to central nervous system (CNS) for the treatment of neurodegenerative disorders: trends and advances. Cent Nerv Syst Agents Med Chem 14(1):43–59
Hamaguchi Y, Xiu Y, Komura K, Nimmerjahn F, Tedder TF (2006) Antibody isotype-specific engagement of Fcgamma receptors regulates B lymphocyte depletion during CD20 immunotherapy. J Exp Med 203(3):743–753
Kasinathan N, Jagani HV, Alex AT, Volety SM, Rao JV (2015) Strategies for drug delivery to the central nervous system by systemic route. Drug Delivery 22(3):243–257
Komori M, Lin YC, Cortese I, Blake A, Ohayon J, Cherup J, Maric D, Kosa P, Wu T, Bielekova B (2016) Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis. Ann Clin Transl Neurol 3(3):166–179
Li T, Dong H, Zhang C, Mo R (2018) Cell-based drug delivery systems for biomedical applications. Nano Res 11(10):5240–5257
Matsushita T, Yanaba K, Bouaziz J-D, Fujimoto M, Tedder TF (2008) Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J Clin Invest 118(10):3420–3430
Nance E, Timbie K, Miller GW, Song J, Louttit C, Klibanov AL, Shih TY, Swaminathan G, Tamargo RJ, Woodworth GF, Hanes J, Price RJ (2014) Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused ultrasound. J Control Release 189:123–132
Nimmerjahn F, Ravetch JV (2006) Fcgamma receptors: old friends and new family members. Immunity. 24(1):19–28
Rubenstein JL, Combs D, Rosenberg J, Levy A, McDermott M, Damon L, Ignoffo R, Aldape K, Shen A, Lee D, Grillo-Lopez A, Shuman MA (2003) Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment. Blood. 101(2):466–468
Uchida J, Hamaguchi Y, Oliver JA, Ravetch JV, Poe JC, Haas KM, Tedder TF (2004) The innate mononuclear phagocyte network depletes B lymphocytes through fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med 199(12):1659–1669
Weber MS, Prod’homme T, Patarroyo JC et al (2010) B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity. Ann Neurol 68(3):369–383
Zhang T-T, Li W, Meng G, Wang P, Liao W (2016) Strategies for transporting nanoparticles across the blood-brain barrier. Biomater Sci 4(2):219–229
Zhou Y, Peng Z, Seven ES, Leblanc RM (2018) Crossing the blood-brain barrier with nanoparticles. J Control Release 270:290–303
Acknowledgements
We are particularly grateful to Laura Ballerini for the critical revision.
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This work was in part supported by Regione Toscana, project INSIDE, FESR 2014–2020.
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Cericol Research Center Colorobbia (Italy) provided nanoparticles, named NBR, used in this work.
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Carnasciali, A., Amoriello, R., Bonechi, E. et al. T Cell Delivery of Nanoparticles-Bound Anti-CD20 Monoclonal Antibody: Successful B Cell Depletion in the Spinal Cord during Experimental Autoimmune Encephalomyelitis. J Neuroimmune Pharmacol 16, 376–389 (2021). https://doi.org/10.1007/s11481-020-09931-w
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DOI: https://doi.org/10.1007/s11481-020-09931-w