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Bispecific T cell engager therapy for refractory rheumatoid arthritis

Nature Medicine volume 30, pages 1593–1601 (2024)Cite this article

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Abstract

Bispecific T cell engagers (BiTEs) kill B cells by engaging T cells. BiTEs are highly effective in acute lymphoblastic leukemia. Here we treated six patients with multidrug-resistant rheumatoid arthritis (RA) with the CD19xCD3 BiTE blinatumomab under compassionate use. Low doses of blinatumomab led to B cell depletion and concomitant decrease of T cells, documenting their engager function. Treatment was safe, with brief increase in body temperature and acute phase proteins during first infusion but no signs of clinically relevant cytokine-release syndrome. Blinatumomab led to a rapid decline in RA clinical disease activity in all patients, improved synovitis in ultrasound and FAPI-PET-CT and reduced autoantibodies. High-dimensional flow cytometry analysis of B cells documented an immune reset with depletion of activated memory B cells, which were replaced by nonclass-switched IgD-positive naïve B cells. Together, these data suggest the feasibility and potential for BiTEs to treat RA. This approach warrants further exploration on other B-cell-mediated autoimmune diseases.

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Fig. 1: Treatment schedule and tolerability of blinatumomab in RA.
Fig. 2: Blinatumomab leads to deep remodeling in the B cell compartment.
Fig. 3: Clinical efficacy of blinatumomab therapy in RA.
Fig. 4: Changes in autoantibodies during blinatumomab therapy.

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Data availability

All numerical data in this paper can be obtained from the corresponding author within 4 weeks upon request via email to georg.schett@uk-erlangen.de. Patient data can be shared only in pseudonymized form. Otherwise, there are no restrictions to data access. All data graphs in the figures (Figs. 1b–f, 2a,e–g, 3a–e,i and 4a–i and Extended Data Figs. 1, 2a–g and 3a–m) show raw data and depict individual values. Source data are provided with this paper.

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Acknowledgements

We thank J. Verhagen and A. Wegner for performing tissue imaging, H. Bang (Orgentec) for performing antimodified peptide autoantibody measurements and T. Winkler for helpful discussions. This study was supported by the Deutsche Forschungsgemeinschaft (DFG) through the Leibniz Award (G.S.), GR 5979/2-1 (R.G.-B.), the research group FOR2886 and the CRC1181, CRC1483, CRC/TRR305 and CRC/TRR221, the Else Kröner-Fresenius-Stiftung through 2022_EKEA.72 (to R.G.-B.) and the IZKF Erlangen (grant N10, to R.G.-B.). Further funding has been obtained from the Bundesministerium für Bildung und Forschung through the MASCARA project and the European Union (ERC Synergy grant 4D Nanoscope). We also acknowledge funding from Staedtler Stiftung.

Author information

Author notes

  1. These authors contributed equally: Laura Bucci, Melanie Hagen.

  2. These authors jointly supervised this work: Georg Schett, Ricardo Grieshaber-Bouyer.

Authors and Affiliations

  1. Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany

    Laura Bucci, Melanie Hagen, Tobias Rothe, Maria Gabriella Raimondo, Filippo Fagni, Carlo Tur, Andreas Wirsching, Jochen Wacker, Artur Wilhelm, Jean-Philippe Auger, Milena Pachowsky, Gerhard Krönke, Stefan Uderhardt, Aline Bozec, Georg Schett & Ricardo Grieshaber-Bouyer

  2. Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany

    Laura Bucci, Melanie Hagen, Tobias Rothe, Maria Gabriella Raimondo, Filippo Fagni, Andreas Wirsching, Jochen Wacker, Jean-Philippe Auger, Milena Pachowsky, Stefan Uderhardt, Aline Bozec, Georg Schett & Ricardo Grieshaber-Bouyer

  3. Department of Rheumatology, Fondazione Policlinico Universitario A Gemelli, IRCSS, Catholic University of Sacred Heart, Rome, Italy

    Carlo Tur, Stefano Alivernini, Angelo Zoli, Maria-Antonietta D’Agostino & Georg Schett

  4. Department of Rheumatology, Charite, Berlin, Germany

    Artur Wilhelm & Gerhard Krönke

  5. Department of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany

    Markus Eckstein

  6. Karolinska Institutet, Stockholm, Sweden

    Georg Schett

Authors
  1. Laura Bucci
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Contributions

L.B., M.H., G.S. and R.G.-B. conceived the study and contributed to the study design. L.B., M.H., G.S. and R.G.-B. performed clinical and experimental data generation and statistical analysis. T.R., M.G.R., F.F., C.T., A. Wirsching, J.W., A. Wilhelm, J.-P.A., M.P., M.E., S.A., A.Z., G.K., S.U., A.B. and M.-A.D’A. contributed to clinical data generation, data analysis, interpretation and writing. All authors contributed to data interpretation and edited the paper.

Corresponding author

Correspondence to Georg Schett.

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Competing interests

There are no conflicts of interest related to this study. The study received no commercial funding. M.-A.D.’A. has received speaker honoraria from Abbvie, Novartis and Janssen, which were not related to this study. G.S. has received speaker honoraria from Janssen and Novartis, which were not related to this study. The other authors declare no competing interests.

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Nature Medicine thanks Lihua Budde, David Fox and Deepak Rao for their contribution to the peer review of this work. Primary Handling Editor: Saheli Sadanand, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Acute phase cytokines by individual patient.

Serum cytokines were analyzed by Luminex assay (N = 6 for time points T0, T2, T3, T5 and N = 4 for time points T1, T4).

Extended Data Fig. 2 T cell subsets after blinatumomab treatment in RA.

Effects of blinatumomab on (a) CD4+ and CD8 + T cells, (b) the CD4/CD8 ratio, (c) the proportion of naïve, effector memory (EM) and central memory (CM) CD4 + T cells, (d) the proportion of naïve, effector memory (EM) and central memory (CM) CD8 + T cells, (e) terminally differentiated effector memory CD4+ cells re-expressing CD45RA (TEMRA) (f) Foxp3+ regulatory T cells, (g) terminally differentiated effector memory CD8+ cells re-expressing CD45RA (TEMRA), (h) RORgt+ Th17 cells. N = 5 individual patients. Dark line depicts the median.

Extended Data Fig. 3 24 week follow-up after blinatumomab therapy during abatacept maintenance.

(a) tender joint count, (b) swollen joint count, (c) patient global disease activity (visual analogue scale; 0–100) and (d) disease activity score 28 (DAS28). Hatched lines show cut-off for remission (2.6). (e) rheumatoid factor, (f) anti-cyclic citrullinated peptide (CCP)-2 autoantibodies, (g) anti-citrullinated, (h) anti-carbamylated, (i) anti-acetylated vimentin autoantibodies and (j) non-modified vimentin autoantibodies (control) (k) immunoglobulin G, (l) immunoglobulin A and (m) immunoglobulin M levels. N = 6 individual patients. Dark line depicts the median.

Extended Data Table 1 B cell panel
Full size table
Extended Data Table 2 T cell panel
Full size table
Extended Data Table 3 Immunohistochemistry antibody specifications
Full size table

Supplementary information

Reporting Summary

Supplementary Data 1

Source data for Extended Data Fig. 1.

Supplementary Data 2

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Supplementary Data 3

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Source data

Source Data Fig. 1

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Source Data Fig. 2

Source data for Fig. 2.

Source Data Fig. 3

Source data for Fig. 3.

Source Data Fig. 4

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Bucci, L., Hagen, M., Rothe, T. et al. Bispecific T cell engager therapy for refractory rheumatoid arthritis. Nat Med 30, 1593–1601 (2024). https://doi.org/10.1038/s41591-024-02964-1

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