T-cell engagers redirect T-cell cytotoxicity for precision cell depletion and are emerging as a promising therapeutic method in autoimmune diseases.1-4 Teclistamab, a bispecific antibody approved for multiple myeloma,5 binds to CD3 on T cells and to B-cell maturation anti-gen (BCMA) on B cells and plasma cells. Here, we report on the safety and efficacy of teclista-mab in 10 patients with six different refractory autoimmune diseases, with up to 15 months of follow-up.
The patients — all of whom had active, multi-drug-resistant autoimmune diseases with charac-teristic serologic profiles — received teclistamab therapy under compassionate use (Table 1). The median age of the patients was 55 years (range, 24 to 66); 60% of the patients were women. Five-month follow-up has been reported previously3for Patients 1 through 4; these patients are in-cluded in this report with 10 to 15 months of fol-low-up.3 All the patients had a history of treatment failure with more than three immunomodula-tory drugs (Table S1 in the Supplementary Ap-pendix, available with the full text of this letter at NEJM.org). Notably, nine patients had received previous B-cell depletion with rituximab.Teclistamab was administered as standard step-up dosing during a 5-day period in an inpa-tient setting (at a dose of 0.06 mg per kilogram of body weight on day 1, 0.3 mg per kilogram on day 3, and 1.5 mg per kilogram on day 5). The initial administration of teclistamab was followed by a one-time maintenance dose of 1.5 mg per kilogram after 4 weeks, as described previous-ly3 (see the Supplementary Appendix). Two weeks before the initiation of teclistamab, glucocorti-coids were tapered to less than 5 mg per day, and all other immunosuppressive medication was stopped.Teclistamab induced rapid B-cell depletion, with a median B-cell aplasia of 157 days (Fig. S1A in the Supplementary Appendix). Free kappa and lambda light chains dropped below detection limits in all the patients (Fig. S1B and S1C), which indicated successful depletion of the plas-ma-cell compartment, and serum immunoglobu-lin levels substantially decreased (Fig. S1D, S1E, and S1F).
Cytokine release syndrome occurred in 8 pa-tients (grade 1 in 4 patients and grade 2 in 4 patients) within 2 days after induction therapy and resolved with a single dose of tocilizumab. No grade 3 or 4 cytokine release syndrome and no neurotoxicity occurred. Mild upper respiratory tract infections were common (in 8 of 10 pa-tients) (Table 1). Patient 1 received inpatient hy-dration to treat viral gastroenteritis. Two bacterial infections warranted antibiotic therapy (Clostridi-um dif f icile infection in Patient 7 and urinary tract infection in Patient 3). Hypogammaglobulinemia developed in all 10 patients, with a median onset of 4 weeks after induction therapy; all cases were treated with a median of two immune globulin infusions.Levels of disease-specific autoantibodies de-creased, and seroconversion was observed for multiple antibodies, including Scl-75, Scl-100, RF, SS-A, PM75, Mi2a, and Mi2 (Fig. S2). In Patients 9 and 10 who had IgG4-related disease, levels of IgG4 and C-reactive protein (markers of humoral inf lammation) normalized (Fig. S2), a change that was accompanied by a substantial improve-ment in constitutional symptoms.Clinical responses were observed in all but 1 patient (Patient 8) (Fig. S3A). Among the 5 pa-tients with interstitial lung disease for whom lon-gitudinal data on pulmonary diffusion capacity were available, symptoms abated and diffusion capacity improved in 4 patients, whereas both measures worsened in 1 patient, with an overall average change from a median carbon monoxide transfer coefficient of 45% to 53% (Fig. S3A). In the patient with Graves disease, magnetic reso-nance imaging showed reduced exophthalmos and muscle thickness (Fig. S3B). In Patient 9, who had IgG4-related disease, FAPI-PET-CT (fibro-blast activation protein inhibitor–positron-emis-sion tomography–computed tomography) showed reduced stromal-cell activation in the tissue (Fig. S3C). At the latest follow-up, 6 of 7 patients who were evaluated were not taking glucocorti-coids, and 8 of 10 patients were not taking im-munosuppressants (Table S1).After a single treatment course, 6 patients were in drug-free remission, with a median recorded response of 11 months (range, 8 to 15); 3 patients had progression after a median of 5 months (Fig. S3D). In 2 patients, teclistamab was administered again, which was followed by a second response. The median duration of response across all pa-tients was 10 months (range, 4 to 15), without concomitant glucocorticoid and immunomodu-latory therapy.
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