Inebilizumab, a B Cell-Depleting Anti-CD19 Antibody for the Treatment of Autoimmune Neurological Diseases: Insights from Preclinical Studies

Ding Chen, Sandra Gallagher, Nancy L Monson, Ronald Herbst, Yue Wang, Ding Chen, Sandra Gallagher, Nancy L Monson, Ronald Herbst, Yue Wang

Abstract

Exaggerated or inappropriate responses by B cells are an important feature in many types of autoimmune neurological diseases. The recent success of B-cell depletion in the treatment of multiple sclerosis (MS) has stimulated the development of novel B-cell-targeting therapies with the potential for improved efficacy. CD19 has emerged as a promising target for the depletion of B cells as well as CD19-positive plasmablasts and plasma cells. Inebilizumab (MEDI-551), an anti-CD19 antibody with enhanced antibody-dependent cell-mediated cytotoxicity against B cells, is currently being evaluated in MS and neuromyelitis optica. This review discusses the role of B cells in autoimmune neurological disorders, summarizes the development of inebilizumab, and analyzes the recent results for inebilizumab treatment in an autoimmune encephalitis mouse model. The novel insights obtained from these preclinical studies can potentially guide future investigation of inebilizumab in patients.

Keywords: B-cell depletion; CD19; autoimmunity; multiple sclerosis; neuromyelitis optica.

Conflict of interest statement

D.C. and N.L.M. declare no conflict of interest. S.G., R.H., and Y.W. are employees of MedImmune.

References

    1. Steinman L. Immunology of relapse and remission in multiple sclerosis. Annu. Rev. Immunol. 2014;32:257–281. doi: 10.1146/annurev-immunol-032713-120227.
    1. Zatonska M.J., Lyszczarz A.K., Michalak S., Kozubski W. The Immunology of Neuromyelitis Optica-Current Knowledge, Clinical Implications, Controversies and Future Perspectives. Int. J. Mol. Sci. 2016;17:273. doi: 10.3390/ijms17030273.
    1. Gilhus N.E., Skeie G.O., Romi F., Lazaridis K., Zisimopoulou P., Tzartos S. Myasthenia gravis—Autoantibody characteristics and their implications for therapy, Nature reviews. Neurology. 2016;12:259–268.
    1. Dowben J.S., Kowalski P.C., Keltner N.L. Biological Perspectives: Anti-NMDA Receptor Encephalitis. Perspect. Psychiatr. Care. 2015;51:236–240. doi: 10.1111/ppc.12132.
    1. Kruse J.L., Lapid M.I., Lennon V.A., Klein C.J., Toole O.O., Pittock S.J., Strand E.A., Frye M.A., McKeon A. Psychiatric Autoimmunity: N-Methyl-d-Aspartate Receptor IgG and Beyond. Psychosomatics. 2015;56:227–241. doi: 10.1016/j.psym.2015.01.003.
    1. Milo R. Therapeutic strategies targeting B-cells in multiple sclerosis. Autoimmun. Rev. 2016;15:714–718. doi: 10.1016/j.autrev.2016.03.006.
    1. Ireland S.J., Blazek M., Harp C.T., Greenberg B., Frohman E.M., Davis L.S., Monson N.L. Antibody-independent B cell effector functions in relapsing remitting multiple sclerosis: Clues to increased inflammatory and reduced regulatory B cell capacity. Autoimmunity. 2012;45:400–414. doi: 10.3109/08916934.2012.665529.
    1. Bennett J.L., O’Connor K.C., Bar-Or A., Zamvil S.S., Hemmer B., Tedder T.F., von Budingen H.C., Stuve O., Yeaman M.R., Smith T.J., et al. B lymphocytes in neuromyelitis optica. Neurol. Neuroimmunol. Neuroinflamm. 2015;2:e104. doi: 10.1212/NXI.0000000000000104.
    1. Fraussen J., de Bock L., Somers V. B cells and antibodies in progressive multiple sclerosis: Contribution to neurodegeneration and progression. Autoimmun. Rev. 2016;15:896–899. doi: 10.1016/j.autrev.2016.07.008.
    1. Hinson S.R., Romero M.F., Popescu B.F., Lucchinetti C.F., Fryer J.P., Wolburg H., Becker P.F., Noell S., Lennon V.A. Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes. Proc. Natl. Acad. Sci. USA. 2012;109:1245–1250. doi: 10.1073/pnas.1109980108.
    1. Bruck W., Popescu B., Lucchinetti C.F., Plese S.M., Gold R., Thal D.R., Metz I. Neuromyelitis optica lesions may inform multiple sclerosis heterogeneity debate. Ann. Neurol. 2012;72:385–394. doi: 10.1002/ana.23621.
    1. Nytrova P., Potlukova E., Kemlink D., Woodhall M., Horakova D., Waters P., Havrdova E., Zivorova D., Vincent A., Trendelenburg M. Complement activation in patients with neuromyelitis optica. J. Neuroimmunol. 2014;274:185–191. doi: 10.1016/j.jneuroim.2014.07.001.
    1. Ratelade J., Zhang H., Saadoun S., Bennett J.L., Papadopoulos M.C., Verkman A.S. Neuromyelitis optica IgG and natural killer cells produce NMO lesions in mice without myelin loss. Acta Neuropathol. 2012;123:861–872. doi: 10.1007/s00401-012-0986-4.
    1. Icoz S., Tuzun E., Kurtuncu M., Durmus H., Mutlu M., Eraksoy M., Demir G.A. Enhanced IL-6 production in aquaporin-4 antibody positive neuromyelitis optica patients. Int. J. Neurosci. 2010;120:71–75. doi: 10.3109/00207450903428970.
    1. Keijzers M., Gadea G.N., de Baets M. Clinical and scientific aspects of acetylcholine receptor myasthenia gravis. Curr. Opin. Neurol. 2014;27:552–557. doi: 10.1097/WCO.0000000000000125.
    1. Hughes E.G., Peng X., Gleichman A.J., Lai M., Zhou L., Tsou R., Parsons T.D., Lynch D.R., Dalmau J., Gordon R.J.B. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J. Neurosci. 2010;30:5866–5875. doi: 10.1523/JNEUROSCI.0167-10.2010.
    1. Michel L., Touil H., Pikor N.B., Gommerman J.L., Prat A., Bar-Or A. B Cells in the Multiple Sclerosis Central Nervous System: Trafficking and Contribution to CNS-Compartmentalized Inflammation. Front. Immunol. 2015;6:636. doi: 10.3389/fimmu.2015.00636.
    1. Lund F.E. Cytokine-producing B lymphocytes-key regulators of immunity. Curr. Opin. Immunol. 2008;20:332–338. doi: 10.1016/j.coi.2008.03.003.
    1. Li R., Rezk A., Miyazaki Y., Hilgenberg E., Touil H., Shen P., Moore C.S., Michel L., Althekair F., Rajasekharan S., et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci. Transl. Med. 2015;7:310ra166. doi: 10.1126/scitranslmed.aab4176.
    1. Croxford A.L., Spath S., Becher B. GM-CSF in Neuroinflammation: Licensing Myeloid Cells for Tissue Damage. Trends Immunol. 2015;36:651–662. doi: 10.1016/j.it.2015.08.004.
    1. Noster R., Riedel R., Mashreghi M.F., Radbruch H., Harms L., Haftmann C., Chang H.D., Radbruch A., Zielinski C.E. IL-17 and GM-CSF expression are antagonistically regulated by human T helper cells. Sci. Transl. Med. 2014;6:241ra280. doi: 10.1126/scitranslmed.3008706.
    1. Tian J., Zekzer D., Hanssen L., Lu Y., Olcott A., Kaufman D.L. Lipopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice. J. Immunol. 2001;167:1081–1089. doi: 10.4049/jimmunol.167.2.1081.
    1. Yanaba K., Bouaziz J.D., Haas K.M., Poe J.C., Fujimoto M., Tedder T.F. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity. 2008;28:639–650. doi: 10.1016/j.immuni.2008.03.017.
    1. Iwata Y., Matsushita T., Horikawa M., Dilillo D.J., Yanaba K., Venturi G.M., Szabolcs P.M., Bernstein S.H., Magro C.M., Williams A.D., et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood. 2011;117:530–541. doi: 10.1182/blood-2010-07-294249.
    1. Shen P., Roch T., Lampropoulou V., O’Connor R.A., Stervbo U., Hilgenberg E., Ries S., Dang V.D., Jaimes Y., Daridon C., et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature. 2014;507:366–370. doi: 10.1038/nature12979.
    1. Knippenberg S., Peelen E., Smolders J., Thewissen M., Menheere P., Tervaert J.W.C., Hupperts R., Damoiseaux J. Reduction in IL-10 producing B cells (Breg) in multiple sclerosis is accompanied by a reduced naive/memory Breg ratio during a relapse but not in remission. J. Neuroimmunol. 2011;239:80–86. doi: 10.1016/j.jneuroim.2011.08.019.
    1. Quan C., Yu H., Qiao J., Xiao B., Zhao G., Wu Z., Li Z., Lu C. Impaired regulatory function and enhanced intrathecal activation of B cells in neuromyelitis optica: Distinct from multiple sclerosis. Mult. Scler. 2013;19:289–298. doi: 10.1177/1352458512454771.
    1. Yang F., Huang D., Cheng C., Wu W. Proportion and significance of CD1d(hi)CD5+CD19+ regulatory B cell in peripheral blood of patients with neuromyelitis optica. Chin. J. Cell. Mol. Immunol. 2015;31:375–378.
    1. Sun F., Ladha S.S., Yang L., Liu Q., Shi S.X., Su N., Bomprezzi R., Shi F.D. Interleukin-10 producing-B cells and their association with responsiveness to rituximab in myasthenia gravis. Muscle Nerve. 2014;49:487–494. doi: 10.1002/mus.23951.
    1. Guptill J.T., Yi J.S., Sanders D.B., Guidon A.C., Juel V.C., Massey J.M., Howard J.F., Jr., Scuderi F., Bartoccioni E., Evoli A., et al. Characterization of B cells in muscle-specific kinase antibody myasthenia gravis. Neurol. Neuroimmunol. Neuroinflamm. 2015;2:e77. doi: 10.1212/NXI.0000000000000077.
    1. Michel L., Chesneau M., Manceau P., Genty A., Garcia A., Salou M., Ngono A.E., Pallier A., Foucher M.J., Lefrere F., et al. Unaltered regulatory B-cell frequency and function in patients with multiple sclerosis. Clin. Immunol. 2014;155:198–208. doi: 10.1016/j.clim.2014.09.011.
    1. Korniotis S., Gras C., Letscher H., Montandon R., Megret J., Siegert S., Ezine S., Fallon P.G., Luther S.A., Fillatreau S., et al. Treatment of ongoing autoimmune encephalomyelitis with activated B-cell progenitors maturing into regulatory B cells. Nat. Commun. 2016;7:12134. doi: 10.1038/ncomms12134.
    1. Serafini B., Rosicarelli B., Magliozzi R., Stigliano E., Aloisi F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 2004;14:164–174. doi: 10.1111/j.1750-3639.2004.tb00049.x.
    1. Magliozzi R., Howell O., Vora A., Serafini B., Nicholas R., Puopolo M., Reynolds R., Aloisi F. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2007;130:1089–1104. doi: 10.1093/brain/awm038.
    1. Pikor N.B., Prat A., Bar-Or A., Gommerman J.L. Meningeal Tertiary Lymphoid Tissues and Multiple Sclerosis: A Gathering Place for Diverse Types of Immune Cells during CNS Autoimmunity. Front. Immunol. 2015;6:657. doi: 10.3389/fimmu.2015.00657.
    1. Sanz I. Rationale for B cell targeting in SLE. Semin. Immunopathol. 2014;36:365–375. doi: 10.1007/s00281-014-0430-z.
    1. Tedder T.F. CD19: A promising B cell target for rheumatoid arthritis. Nat. Rev. Rheumatol. 2009;5:572–577. doi: 10.1038/nrrheum.2009.184.
    1. Bluml S., McKeever K., Ettinger R., Smolen J., Herbst R. B-cell targeted therapeutics in clinical development. Arthr. Res. Ther. 2013;15:S4. doi: 10.1186/ar3906.
    1. Halliley J.L., Tipton C.M., Liesveld J., Rosenberg A.F., Darce J., Gregoretti I.V., Popova L., Kaminiski D., Fucile C.F., Albizua I., et al. Long-Lived Plasma Cells Are Contained within the CD19−CD38(hi)CD138+ Subset in Human Bone Marrow. Immunity. 2015;43:132–145. doi: 10.1016/j.immuni.2015.06.016.
    1. Mei H.E., Wirries I., Frolich D., Brisslert M., Giesecke C., Grun J.R., Alexander T., Schmidt S., Luda K., Kuhl A.A., et al. A unique population of IgG-expressing plasma cells lacking CD19 is enriched in human bone marrow. Blood. 2015;125:1739–1748. doi: 10.1182/blood-2014-02-555169.
    1. Schuh E., Berer K., Mulazzani M., Feil K., Meinl I., Lahm H., Krane M., Lange R., Pfannes K., Subklewe M., et al. Features of Human CD3+CD20+ T Cells. J. Immunol. 2016 doi: 10.4049/jimmunol.1600089.
    1. Hammer O. CD19 as an attractive target for antibody-based therapy. MAbs. 2012;4:571–577. doi: 10.4161/mabs.21338.
    1. Herbst R., Wang Y., Gallagher S., Mittereder N., Kuta E., Damschroder M., Woods R., Rowe D.C., Cheng L., Cook K., et al. B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. J. Pharmacol. Exp. Ther. 2010;335:213–222. doi: 10.1124/jpet.110.168062.
    1. Schiopu E., Chatterjee S., Hsu V., Flor A., Cimbora D., Patra K., Yao W., Li J., Streicher K., McKeever K., et al. Safety and tolerability of an anti-CD19 monoclonal antibody, MEDI-551, in subjects with systemic sclerosis: A phase I, randomized, placebo-controlled, escalating single-dose study. Arthr. Res. Ther. 2016;18:131. doi: 10.1186/s13075-016-1021-2.
    1. Yazawa N., Hamaguchi Y., Poe J.C., Tedder T.F. Immunotherapy using unconjugated CD19 monoclonal antibodies in animal models for B lymphocyte malignancies and autoimmune disease. Proc. Natl. Acad. Sci. USA. 2005;102:15178–15183. doi: 10.1073/pnas.0505539102.
    1. Streicher K., Morehouse C.A., Groves C.J., Rajan B., Pilataxi F., Lehmann K.P., Brohawn P.Z., Higgs B.W., McKeever K., Greenberg S.A., et al. The plasma cell signature in autoimmune disease. Arthr. Rheumatol. 2014;66:173–184. doi: 10.1002/art.38194.
    1. Gallagher S., Yusuf I., McCaughtry T.M., Turman S., Sun H., Kolbeck R., Herbst R., Wang Y. MEDI-551 Treatment Effectively Depletes B Cells and Reduces Serum Titers of Autoantibodies in Mice Transgenic for Sle1 and Human CD19. Arthr. Rheumatol. 2016;68:965–976. doi: 10.1002/art.39503.
    1. Gallagher S., Turman S., Yusuf I., Akhgar A., Wu Y., Roskos L.K., Herbst R., Wang Y. Pharmacological profile of MEDI-551, a novel anti-CD19 antibody, in human CD19 transgenic mice. Int. Immunopharmacol. 2016;36:205–212. doi: 10.1016/j.intimp.2016.04.035.
    1. Yusuf I., Stern J., McCaughtry T.M., Gallagher S., Sun H., Gao C., Tedder T., Carlesso G., Carter L., Herbst R., et al. Germinal center B cell depletion diminishes CD4+ follicular T helper cells in autoimmune mice. PLoS ONE. 2014;9:e102791. doi: 10.1371/journal.pone.0102791.
    1. Constantinescu C.S., Farooqi N., O’Brien K., Gran B. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS) Br. J. Pharmacol. 2011;164:1079–1106. doi: 10.1111/j.1476-5381.2011.01302.x.
    1. Robinson A.P., Harp C.T., Noronha A., Miller S.D. The experimental autoimmune encephalomyelitis (EAE) model of MS: Utility for understanding disease pathophysiology and treatment. Handb. Clin. Neurol. 2014;122:173–189.
    1. Horn K.L., Kronsbein H.C., Weber M.S. Targeting B cells in the treatment of multiple sclerosis: Recent advances and remaining challenges. Ther. Adv. Neurol. Disord. 2013;6:161–173. doi: 10.1177/1756285612474333.
    1. Hjelmstrom P., Juedes A.E., Fjell J., Ruddle N.H. B-cell-deficient mice develop experimental allergic encephalomyelitis with demyelination after myelin oligodendrocyte glycoprotein sensitization. J. Immunol. 1998;161:4480–4483.
    1. Lyons J.A., San M., Happ M.P., Cross A.H. B cells are critical to induction of experimental allergic encephalomyelitis by protein but not by a short encephalitogenic peptide. Eur. J. Immunol. 1999;29:3432–3439. doi: 10.1002/(SICI)1521-4141(199911)29:11<3432::AID-IMMU3432>;2-2.
    1. Challa D.K., Bussmeyer U., Khan T., Montoyo H.P., Bansal P., Ober R.J., Ward E.S. Autoantibody depletion ameliorates disease in murine experimental autoimmune encephalomyelitis. MAbs. 2013;5:655–659. doi: 10.4161/mabs.25439.
    1. Ramanathan S., Dale R.C., Brilot F. Anti-MOG antibody: The history, clinical phenotype, and pathogenicity of a serum biomarker for demyelination. Autoimmun. Rev. 2016;15:307–324. doi: 10.1016/j.autrev.2015.12.004.
    1. Molnarfi N., Topphoff U.S., Weber M.S., Patarroyo J.C., Prod’homme T., Doyer M.Z., Shetty A., Linington C., Slavin A.J., Hidalgo J., et al. MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies. J. Exp. Med. 2013;210:2921–2937. doi: 10.1084/jem.20130699.
    1. Lafaille J.J., Nagashima K., Katsuki M., Tonegawa S. High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice. Cell. 1994;78:399–408. doi: 10.1016/0092-8674(94)90419-7.
    1. Bettelli E., Baeten D., Jager A., Sobel R.A., Kuchroo V.K. Myelin oligodendrocyte glycoprotein-specific T and B cells cooperate to induce a Devic-like disease in mice. J. Clin. Investig. 2006;116:2393–2402. doi: 10.1172/JCI28334.
    1. Krishnamoorthy G., Lassmann H., Wekerle H., Holz A. Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation. J. Clin. Investig. 2006;116:2385–2392. doi: 10.1172/JCI28330.
    1. Weber M.S., Prod’homme T., Patarroyo J.C., Molnarfi N., Karnezis T., Horn K.L., Danilenko D.M., Anderson J.E., Slavin A.J., Linington C., et al. B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity. Ann. Neurol. 2010;68:369–383. doi: 10.1002/ana.22081.
    1. Monson N.L., Cravens P., Hussain R., Harp C.T., Cummings M., Martin M.D., Ben L.H., Do J., Lyons J.A., Racke A.L., et al. Rituximab therapy reduces organ-specific T cell responses and ameliorates experimental autoimmune encephalomyelitis. PLoS ONE. 2011;6:e17103. doi: 10.1371/journal.pone.0017103.
    1. Chen D., Blazek M., Ireland S., Ortega S., Kong X., Meeuwissen A., Stowe A., Carter L., Wang Y., Herbst R., et al. Single dose of glycoengineered anti-CD19 antibody (MEDI551) disrupts experimental autoimmune encephalomyelitis by inhibiting pathogenic adaptive immune responses in the bone marrow and spinal cord while preserving peripheral regulatory mechanisms. J. Immunol. 2014;193:4823–4832. doi: 10.4049/jimmunol.1401478.
    1. Chen D., Ireland S.J., Davis L.S., Kong X., Stowe A.M., Wang Y., White W.I., Herbst R., Monson N.L. Autoreactive CD19+CD20− Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis. J. Immunol. 2016;196:1541–1549. doi: 10.4049/jimmunol.1501376.
    1. Matsushita T., Yanaba K., Bouaziz J.D., Fujimoto M., Tedder T.F. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J. Clin. Investig. 2008;118:3420–3430. doi: 10.1172/JCI36030.
    1. Horn K.L., Schleich E., Hertzenberg D., Hapfelmeier A., Kumpfel T., von Bubnoff N., Hohlfeld R., Berthele A., Hemmer B., Weber M.S. Anti-CD20 B-cell depletion enhances monocyte reactivity in neuroimmunological disorders. J. Neuroinflamm. 2011;8:146. doi: 10.1186/1742-2094-8-146.
    1. Weber M.S., Hemmer B., Cepok S. The role of antibodies in multiple sclerosis. Biochim. Biophys. Acta. 2011;1812:239–245. doi: 10.1016/j.bbadis.2010.06.009.
    1. Krumbholz M., Derfuss T., Hohlfeld R., Meinl E. B cells and antibodies in multiple sclerosis pathogenesis and therapy. Nat. Rev. Neurol. 2012;8:613–623. doi: 10.1038/nrneurol.2012.203.
    1. Owens G.P., Bennett J.L., Lassmann H., O’Connor K.C., Ritchie A.M., Shearer A., Lam C., Yu X., Birlea M., DuPree C., et al. Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid. Ann. Neurol. 2009;65:639–649. doi: 10.1002/ana.21641.
    1. Williams M.G.M., Ahmed R. B cell memory and the long-lived plasma cell. Curr. Opin. Immunol. 1999;11:172–179. doi: 10.1016/S0952-7915(99)80029-6.
    1. Mahevas M., Michel M., Weill J.C., Reynaud C.A. Long-lived plasma cells in autoimmunity: Lessons from B-cell depleting therapy. Front. Immunol. 2013;4:494. doi: 10.3389/fimmu.2013.00494.
    1. Misumi I., Whitmire J.K. B cell depletion curtails CD4+ T cell memory and reduces protection against disseminating virus infection. J. Immunol. 2014;192:1597–1608. doi: 10.4049/jimmunol.1302661.
    1. Dale R.C., Brilot F., Duffy L.V., Twilt M., Waldman A.T., Narula S., Muscal E., Deiva K., Andersen E., Eyre M.R., et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology. 2014;83:142–150. doi: 10.1212/WNL.0000000000000570.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi