Introduction
Myasthenia gravis (MG) is an antibody-mediated autoimmune disease (AID) that affects the neuromuscular junction, leading to fluctuating muscle weakness and fatigue. It is primarily caused by autoantibodies targeting acetylcholine receptors (AChR), muscle-specific kinase, or low-density lipoprotein receptor-related protein 4 (LRP4). 1 While conventional immunosuppressive therapies and symptomatic treatments provide relief for many patients, a subset of 10%–15% of the patients remains refractory, necessitating novel therapeutic approaches. 2
Refractory MG, particularly associated with rare anti-LRP4 antibodies, presents unique challenges due to its resistance to standard treatments and severe disease burden. 3 , 4 Traditional interventions, including corticosteroids, plasma exchange, intravenous immunoglobulins, and B cell-depletion strategies such as rituximab, often fail to induce long-term remission. Recent advancements have highlighted the potential of deep B cell depletion using CD19- or B cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR)-T cell therapy as a promising option for refractory AIDs, including AChR MG. 5 , 6 , 7 , 8 , 9
An emerging alternative involves the use of bispecific antibodies, which simultaneously target two distinct antigens to enhance immune-mediated clearance of pathogenic cells. This approach with T cell engagers (TCEs) redirecting polyclonal CD3 + T cells against CD19- or BCMA-expressing cells has demonstrated efficacy and safety in AIDs of the rheumatologic spectrum (i.e., systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and myositis), offering a novel mechanism for disease control. 10 , 11 , 12 Teclistamab, a bispecific antibody that binds BCMA and CD3, redirects T cells against plasma cells, effectively depleting antibody-producing B cells. Originally developed for multiple myeloma, teclistamab represents a potential therapeutic candidate for severe autoimmune conditions driven by pathogenic autoantibodies. 13
Here, we report the use of teclistamab in a 47-year-old female patient with severe, refractory, LRP4 + MG, who had failed multiple conventional therapies. Following teclistamab treatment, she experienced rapid and sustained remission, highlighting its potential as a viable therapeutic strategy in refractory MG.
Patient and clinical findings
The diagnosis of double-seronegative MG was made in 2014 and anti-LRP4 antibodies were detected in 2019. Despite multiple treatments, including B cell-depleting monoclonal antibodies (e.g., rituximab), a proteasome inhibitor (e.g., bortezomib), immunosuppressants (e.g., azathioprine, steroids), intravenous immunoglobulin, and immunoadsorption or plasma exchange, she experienced recurrent myasthenic exacerbations and one myasthenic crisis between July 2020 and October 2024, with no sustained stabilization of her disease. When she came to our clinic in August 2024, she was receiving weekly immunoadsorption and taking 480 mg of a cholinesterase inhibitor every day. She was confined to a wheelchair, had difficulty speaking, swallowing, and breathing, and was classified as class IVB according to the Myasthenia Gravis Foundation of America criteria ( Figure 1 A). Additional methodological details are provided in the supplemental material and methods .
In this situation, we opted for off-label use of teclistamab after obtaining the patient’s written informed consent. Teclistamab was administered subcutaneously on days 1 (0.06 mg/kg), 4 (0.3 mg/kg), and 6 (1.5 mg/kg), with 1 maintenance dose of 1.5 mg/kg after 4 weeks.
After the first application, the patient showed signs of cytokine release syndrome (CRS; grade 1 during days 2 and 3, which resolved after a single dose of tocilizumab (8 mg/kg) on day 2. There was no evidence of acute neurotoxicity, and MRI of the brain performed at month 4 showed no pathological findings. Regarding hematotoxicity, the patient presented with a preexisting grade 2 lymphopenia, which showed some fluctuation over the course of treatment but never worsened significantly or persistently ( Figures 1 B and 1C). With regard to the CD4/CD8 ratio, we observed a marked shift in favor of the CD8 population on day 7 of therapy, primarily due to a transiently low number of circulating CD4 + T cells, which dropped below 200/μL only once ( Figure 1 D). Natural killer cell counts remained within the reference range throughout the observation period ( Figure 1 E). Residual circulating B cells were eliminated, anti-LRP4 antibodies were undetectable, and the patient had preexisting hypogammaglobulinemia prior to teclistamab treatment, which worsened after therapy and required repeated immunoglobulin substitution starting from the second month after the first teclistamab administration ( Figure 1 F). Additionally, we observed a decline in tested vaccine titers against measles, rubella, and tetanus, further highlighting the impact of BCMA targeting on humoral immunity ( Figure 1 G).
Most important, all multicomponent disease scores (i.e., quantitative MG [QMG] , MG-activities of daily living [MG-ADL], and revised MG-Quality of Life 15 scale [MG-QoL15r]) showed a rapid and sustained decline during the follow-up period to date. Within just 4 weeks after treatment initiation, the patient showed remarkable progress: walking up to 1 km unassisted and experiencing no difficulties with speech, swallowing, or breathing, with only minor diplopic symptoms remaining. At 3 months, the cholinesterase inhibitor dosage was gradually discontinued, the patient was no longer receiving any immunosuppressive agents, and the walking distance had increased to more than 1.5 km. At 6 months, the patient remained in remission, without evidence of disease or need for further treatment ( Figures 1 H and 1I).
Discussion
In this case report, we demonstrate that short-term therapy with the BCMA × CD3 TCE teclistamab can induce a rapid and sustained remission during a still-limited follow-up period. The concept of T cell-based elimination of B cells in difficult-to-treat AIDs has gained significant attention following initial successful case reports and series on B cell-targeting CAR-T cells. 14 We and other colleagues have published initial successful experiences in MG with CAR-T cells directed against CD19 or BCMA. 5 , 6 , 7 , 8 , 9 A major advantage of CAR-T cells over monoclonal antibodies is their ability to deplete B and/or plasma cells deep within tissues, as demonstrated in recent comparative biopsies from inguinal lymph nodes of treated patients. 15 The extent of depletion achieved by TCEs remains an area of ongoing investigation.
TCEs targeting CD19 (e.g., blinatumomab) and BCMA (e.g., teclistamab) have been successfully used in case series for rheumatologic diseases. 10 , 11 , 12 One advantage of TCEs over autologous CAR-T cells is their off-the-shelf availability. 16 Additionally, data from hematologic-oncologic patient cohorts suggest that TCEs are better tolerated regarding CRS and immune effector cell-associated neurotoxicity syndrome, which is particularly relevant for patients with limited biological reserves. Moreover, TCE therapy does not carry the risk of vector insertion and oncogenic transformation, an area of ongoing investigation in oncology. 17 , 18
Regarding target antigens, BCMA may offer an advantage by effectively eliminating long-lived plasma cells, which in their majority are CD19 − . 19 , 20 , 21 This consideration is particularly relevant in the context of TCEs, which are likely to induce a lower depth of depletion compared to CAR-T cells. While CD19-directed CAR-T cells can indirectly affect plasma cells by eliminating their precursors, this mechanism may be insufficient for TCEs. Targeting BCMA allows direct depletion of the pathogenic plasma cell compartment, thereby compensating for the limited depth of depletion of TCEs, but at the expense of deeper suppression of humoral immunity. Early positive results for an anti-BCMA approach have already been reported in CAR-T cell and TCE studies and case series. 11 , 12 , 22 The mode of action of anti-BCMA TCEs is also fundamentally different from the conventional MG therapies that the patient has received to this point. Monoclonal antibodies such as rituximab deplete CD20 + B cells but do not affect antibody-producing memory B cells, plasmablasts, or plasma cells. Bortezomib can target plasma cells via proteasome inhibition, but clinical responses are often variable and limited by toxicity. Interventions such as intravenous immunoglobulin and immunoadsorption may transiently reduce circulating antibody levels but do not eliminate the underlying autoreactive cells. In contrast, teclistamab directly redirects polyclonal CD3 + T cells to eliminate BCMA-expressing memory B cells, plasmablasts, and plasma cells, resulting in rapid and profound immunologic responses. However, a drawback of BCMA targeting is the more pronounced impairment of humoral immunity, as observed in our patient, including reduced vaccine titers, which aligns with findings from multiple myeloma patients treated with teclistamab. 23 The lymphopenia observed with teclistamab therapy may result from an inflammatory reaction in the bone marrow niche or a redistribution of T cells from peripheral blood to tissues. 24 This latter hypothesis could only be addressed through biopsies of lymph nodes (or alternative B cell niches) to assess T cell redistribution. The profound B cell depletion observed, despite the fact that BCMA expression is largely restricted to memory B cells, plasmablasts, and plasma cells, is seen in patients with AIDs and with malignancies treated with anti-BCMA TCEs. 11 , 12 , 23 Several mechanisms may account for this finding, including bystander killing by local T cell activation, cross-reactivity to structurally related receptors such as transmembrane activator, calcium modulator, and cyclophilin ligand interactor or the BAFF receptor, or the possibility that even minimal BCMA expression levels are sufficient to trigger TCE-mediated cytotoxicity. In addition, targeted elimination of BCMA-expressing cells may disrupt B cell survival niches and indirectly affect broader B cell homeostasis.
In conclusion, this case suggests that short-term treatment with BCMA-targeting TCEs may offer a promising therapeutic strategy for refractory MG. The rapid and sustained remission observed underscores the potential role of teclistamab, warranting further clinical evaluation. Furthermore, this case represents the first use of a T cell-engaging bispecific antibody in an AID of the peripheral nervous system and identifies BCMA as a potential target in the immunotherapy of MG.
Acknowledgments
The study was supported by the European Regional Development Fund (Europäischer Fonds für Regionale Entwicklung [EFRE] project: ZELL-THEMA) to D.M.
Author contributions
S.S. and D.M. designed the study. S.S., M.A.-D., S.V., L.L., D.W., and D.M. acquired and interpreted the data. S.D., T.R., and S.M. helped design the study and write the manuscript. All authors reviewed the manuscript. S.S. and D.M. had final responsibility for verifying the underlying data reported and the decision to submit the manuscript.
Declaration of interests
S.V. has received speaker honoraria from the RGE CME training agency and Klinikum Dessau and has received support for attending meetings from Sponsoring RG. S.D. has received research grants from Kite/Gilead and Roche; consulting fees from Beigene, BMS/Celgene, Johnson & Johnson, and Roche; and support for attending meetings from BMS/Celgene, Johnson & Johnson, Pierre Fabre, and Roche. T.R. has received research grants from Alexion, Biogen, Genzyme, Merck Serono, Novartis, and Roche; consulting fees from Alexion, Argenx, Biogen, Celgene, BMS, Johnson & Johnson, Genzyme, Merck, Novartis, Sanofi, and UCB; honoraria from Alexion, Argenx, Biogen, Celgene, BMS, Johnson & Johnson, Genzyme, Merck, Novartis, Sanofi, and UCB; support for attending meetings from Alexion, Argenx, Merck; and participated in a drug safety monitoring board for Argenx. S.M. has received honoraria for lecturing, travel expenses, and attending meetings from Academy 2, Argenx, Alexion, Almirall, Amicus Therapeutics Germany, AstraZeneca, Bayer Health Care, Biogen, BioNtech, BMS/Celgene, Chugai Pharmaceutical, Datamed, Demecan, Desitin, Diamed, Diaplan, DIU Dresden, DPmed, Gen Medicine and Healthcare products, Genzyme, Hexal AG, IGES, Impulze GmbH, Janssen Cilag, KW Medipoint, MedDay Pharmaceuticals, Medmile, Merck Serono, MICE, Mylan, Neuraxpharm, Neuropoint, Novartis, Novo Nordisk, ONO Pharma, Oxford PharmaGenesis, QuintilesIMS, Roche, Sanofi, Springer Medizin Verlag, STADA, Teva, UCB, Viatris, Wings for Life International, and Xcenda. D.M. has received speaker honoraria and consulting fees from AbbVie, AstraZeneca, AvenCell, BMS, Beigene, Celgene, Galapagos, Gilead, Janssen, Kyverna Therapeutics, Miltenyi Biotec, Novartis, and Roche.
Footnotes
Supplemental information can be found online at https://doi.org/10.1016/j.ymthe.2025.06.029 .
Contributor Information
Stefanie Schreiber, Email: stefanie.schreiber@med.ovgu.de.
Dimitrios Mougiakakos, Email: dimitrios.mougiakakos@med.ovgu.de.
Supplemental information
Document S1. Supplemental material and methods
Document S2. Article plus supplemental information
References
1. Kaminski H.J., Sikorski P., Coronel S.I., Kusner L.L. Myasthenia gravis: the future is here. J. Clin. Invest. 2024;134 doi: 10.1172/JCI179742.
2. Dalakas M.C. Advances in the therapeutic algorithm for myasthenia gravis. Nat. Rev. Neurol. 2023;19:393–394. doi: 10.1038/s41582-023-00825-y.
3. Zhang B., Tzartos J.S., Belimezi M., Ragheb S., Bealmear B., Lewis R.A., Xiong W.C., Lisak R.P., Tzartos S.J., Mei L. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch. Neurol. 2012;69:445–451. doi: 10.1001/archneurol.2011.2393.
4. Rivner M.H., Quarles B.M., Pan J.X., Yu Z., Howard J.F., Jr., Corse A., Dimachkie M.M., Jackson C., Vu T., Small G., et al. Clinical features of LRP4/agrin-antibody-positive myasthenia gravis: A multicenter study. Muscle Nerve. 2020;62:333–343. doi: 10.1002/mus.26985.
5. Granit V., Benatar M., Kurtoglu M., Miljković M.D., Chahin N., Sahagian G., Feinberg M.H., Slansky A., Vu T., Jewell C.M., et al. Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study. Lancet Neurol. 2023;22:578–590. doi: 10.1016/S1474-4422(23)00194-1.
6. Haghikia A., Hegelmaier T., Wolleschak D., Böttcher M., Desel C., Borie D., Motte J., Schett G., Schroers R., Gold R., Mougiakakos D. Anti-CD19 CAR T cells for refractory myasthenia gravis. Lancet Neurol. 2023;22:1104–1105. doi: 10.1016/S1474-4422(23)00375-7.
7. Haghikia A., Hegelmaier T., Wolleschak D., Böttcher M., Pappa V., Motte J., Borie D., Gold R., Feist E., Schett G., Mougiakakos D. Clinical efficacy and autoantibody seroconversion with CD19-CAR T cell therapy in a patient with rheumatoid arthritis and coexisting myasthenia gravis. Ann. Rheum. Dis. 2024;83:1597–1598. doi: 10.1136/ard-2024-226017.
8. Motte J., Sgodzai M., Schneider-Gold C., Steckel N., Mika T., Hegelmaier T., Borie D., Haghikia A., Mougiakakos D., Schroers R., Gold R. Treatment of concomitant myasthenia gravis and Lambert-Eaton myasthenic syndrome with autologous CD19-targeted CAR T cells. Neuron. 2024;112:1757–1763.e2. doi: 10.1016/j.neuron.2024.04.014.
9. Tian D.S., Qin C., Dong M.H., Heming M., Zhou L.Q., Wang W., Cai S.B., You Y.F., Shang K., Xiao J., et al. B cell lineage reconstitution underlies CAR-T cell therapeutic efficacy in patients with refractory myasthenia gravis. EMBO Mol. Med. 2024;16:966–987. doi: 10.1038/s44321-024-00043-z.
10. Bucci L., Hagen M., Rothe T., Raimondo M.G., Fagni F., Tur C., Wirsching A., Wacker J., Wilhelm A., Auger J.P., et al. Bispecific T cell engager therapy for refractory rheumatoid arthritis. Nat. Med. 2024;30:1593–1601. doi: 10.1038/s41591-024-02964-1.
11. Hagen M., Bucci L., Böltz S., Nöthling D.M., Rothe T., Anoshkin K., Raimondo M.G., Tur C., Wirsching A., Wacker J., et al. BCMA-Targeted T-Cell-Engager Therapy for Autoimmune Disease. N. Engl. J. Med. 2024;391:867–869. doi: 10.1056/NEJMc2408786.
12. Alexander T., Krönke J., Cheng Q., Keller U., Krönke G. Teclistamab-Induced Remission in Refractory Systemic Lupus Erythematosus. N. Engl. J. Med. 2024;391:864–866. doi: 10.1056/NEJMc2407150.
13. Moreau P., Garfall A.L., van de Donk N.W.C.J., Nahi H., San-Miguel J.F., Oriol A., Nooka A.K., Martin T., Rosinol L., Chari A., et al. Teclistamab in Relapsed or Refractory Multiple Myeloma. N. Engl. J. Med. 2022;387:495–505. doi: 10.1056/NEJMoa2203478.
14. Schett G., Mackensen A., Mougiakakos D. CAR T-cell therapy in autoimmune diseases. Lancet. 2023;402:2034–2044. doi: 10.1016/S0140-6736(23)01126-1.
15. Tur C., Eckstein M., Velden J., Rauber S., Bergmann C., Auth J., Bucci L., Corte G., Hagen M., Wirsching A., et al. CD19-CAR T-cell therapy induces deep tissue depletion of B cells. Ann. Rheum. Dis. 2025;84:106–114. doi: 10.1136/ard-2024-226142.
16. Mougiakakos D., Meyer E.H., Schett G. CAR T-cells in autoimmunity: game changer or stepping stone? Blood. 2025;145:1841–1849. doi: 10.1182/blood.2024025413.
17. Perica K., Jain N., Scordo M., Patel R., Eren O.C., Patel U., Gundem G., Domenico D., Mitra S., Socci N.D., et al. CD4+ T-Cell Lymphoma Harboring a Chimeric Antigen Receptor Integration in TP53. N. Engl. J. Med. 2025;392:577–583. doi: 10.1056/NEJMoa2411507.
18. Kobbe G., Brüggemann M., Baermann B.N., Wiegand L., Trautmann H., Yousefian S., Libertini S., Menssen H.D., Maier H.J., Ulrich P., et al. Aggressive Lymphoma after CD19 CAR T-Cell Therapy. N. Engl. J. Med. 2024;391:1217–1226. doi: 10.1056/NEJMoa2402730.
19. Mei H.E., Wirries I., Frölich D., Brisslert M., Giesecke C., Grün J.R., Alexander T., Schmidt S., Luda K., Kühl 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.
20. Bhoj V.G., Arhontoulis D., Wertheim G., Capobianchi J., Callahan C.A., Ellebrecht C.T., Obstfeld A.E., Lacey S.F., Melenhorst J.J., Nazimuddin F., et al. Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy. Blood. 2016;128:360–370. doi: 10.1182/blood-2016-01-694356.
21. Baker D.J., Levine B.L., June C.H. Assessing the oncogenic risk: the long-term safety of autologous chimeric antigen receptor T cells. Lancet. 2025;405:751–754. doi: 10.1016/S0140-6736(25)00039-X.
22. Muller F., Wirsching A., Hagen M., Volkl S., Tur C., Raimondo M.G., Taubmann J., Bucci L., Zhang L., Kretschmann S., et al. BCMA-CAR T-cells in a patient with relapsing idiopathic inflammatory myositis after CD19-CAR T-cells. Nat. Med. 2025;31:1793–1797. doi: 10.1038/s41591-025-03718-3.
23. Frerichs K.A., Verkleij C.P.M., Mateos M.V., Martin T.G., Rodriguez C., Nooka A., Banerjee A., Chastain K., Perales-Puchalt A., Stephenson T., et al. Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma: importance of immunoglobulin supplementation. Blood Adv. 2024;8:194–206. doi: 10.1182/bloodadvances.2023011658.
24. Firestone R.S., McAvoy D., Shekarkhand T., Serrano E., Hamadeh I., Wang A., Zhu M., Qin W.G., Patel D., Tan C.R., et al. CD8 effector T cells enhance teclistamab response in BCMA-exposed and -naive multiple myeloma. Blood Adv. 2024;8:1600–1611. doi: 10.1182/bloodadvances.2023011225.