Team: Bispecific T-Cell Engagers (BiTEs), aka “Other Drugs BiTE the Dust”
Authors:
- Marwin Groener, Rheumatology Fellow, The Johns Hopkins University School of Medicine
- Maximilian F. Konig, Assistant Professor of Medicine, The Johns Hopkins University School of Medicine
Team Overview:
CAR-T cell therapies promise to change the game of rheumatology. But an upcoming rookie (and MVP in oncology) is our No.1 draft pick this year: Bispecific T cell-engaging antibodies.
Originally scouted by hematologists, these bispecific antibodies bind the T cell receptor-CD3 complex on any T cell with one end and a B cell surface protein (e.g. CD19 or BCMA) on B cells with the other. This dual engagement results in the destruction of B cells by the patient’s own (unmodified) T cells.
In this case study (1), teclistamab, a BCMAxCD3 bispecific T cell engager, was used to treat a patient with refractory SLE (lupus nephritis, hemolytic anemia, rash, oral ulcers, and arthritis). By six weeks, all laboratory (hypocomplementemia, anti-dsDNA) and clinical abnormalities had resolved. Her SLEDAI-2K decreased from 20 to 0, and drug-free complete remission was sustained at 16-week follow-up.
Unlike CAR-T cell therapy, bispecific antibodies offer the potential for deep depletion and “immune reset” of the B-cell compartment without the requirement for apheresis and cell engineering, without cytotoxic conditioning therapy (“lymphodepletion”), and without any risk of secondary malignancies! Like CAR-T cell therapy, side effects included cytokine release syndrome, hypogammaglobulinemia (treated with IVIg), and mild infections.
This “off-the-shelf” therapy has the potential to become the Michael Jordan of rheumatology. Blinatumomab, a CD19xCD3 bispecific T cell engager (BiTE), was also successful in patients with rheumatoid arthritis (2), and teclistamab showed promise in systemic sclerosis, Sjögren’s disease, anti-MDA5-associated dermatomyositis (3). The future holds even more for this promising player that can be engineered to beat any opponent. Bispecific antibody therapies targeting autoreactive B cells in SLE (9G4xCD3 BiTE, 4), antiphospholipid syndrome (BaiTE, 5), and even autoreactive T cells in ankylosing spondylitis (TRBV9xCD3 BiTE, 6) were presented at ACR Convergence 2024, highlighting opportunities for precision targeting without increasing the infection risk.
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References
- Alexander T, Krönke J, Cheng Q, Keller U, Krönke G. Teclistamab-Induced Remission in Refractory Systemic Lupus Erythematosus. N Engl J Med. 2024 Sep 5;391(9):864-866. PMID: 39231352.
- Bucci L, Hagen M, Rothe T, Raimondo MG, Fagni F, Tur C, Wirsching A, Wacker J, Wilhelm A, Auger JP, Pachowsky M, Eckstein M, Alivernini S, Zoli A, Krönke G, Uderhardt S, Bozec A, D’Agostino MA, Schett G, Grieshaber-Bouyer R. Bispecific T cell engager therapy for refractory rheumatoid arthritis. Nat Med. 2024 Jun;30(6):1593-1601. PMID: 38671240.
- Hagen M, Bucci L, Böltz S, Nöthling DM, Rothe T, Anoshkin K, Raimondo MG, Tur C, Wirsching A, Wacker J, Düsing C, Distler JHW, Kuwert T, Bozec A, Ramming A, Schett G, Grieshaber-Bouyer R. BCMA-Targeted T-Cell-Engager Therapy for Autoimmune Disease. N Engl J Med. 2024 Sep 5;391(9):867-869. PMID: 39231353.
- Liu J, Xia Y, Ferris D, Shaw E, Mog B, Pearlman A, Moritz B, Kaeo K, Gliech C, Awosika T, DiNapoli S, Nichakawade T, Li Y, Ge J, Glavaris S, Marcou N, Ahmedna T, Bugrovsky R, Jenks S, Bettegowda C, Goldman D, Petri M, Sanz I, Kinzler K, Zhou S, Vogelstein B, Paul S, Andrade F, Konig M. T Cell-Engaging Bispecific Antibodies to Target Autoreactive 9G4 Idiotope B Cells in Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9).
- Xia Y, Liu J, Pearlman A, Mog B, Shaw E, Kaeo K, Gliech C, Moritz B, Awosika T, DiNapoli S, Glavaris S, Ge J, Nichakawade T, Marcou N, Paul S, Pardoll D, Bettegowda C, Goldman D, Petri M, Rosen A, Kinzler K, Zhou S, Vogelstein B, Konig M. Bispecific Autoantigen-T Cell Engagers (BaiTE) to Selectively Target Autoreactive B Cells in Antiphospholipid Syndrome [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9).
- Glavaris S, Pearlman A, Liu J, Ge J, Xia Y, Kaeo K, Awosika T, Gliech C, Nichakawade T, Marcou N, Bettegowda C, Pardoll D, Kinzler K, Zhou S, Vogelstein B, Paul S, Konig M. TRBV9-Targeted Bispecific T Cell-Engaging Antibodies to Reset the Autoreactive T Cell Compartment in Spondyloarthritis and HLA-DQ8 Celiac Disease [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9).