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Abstract Number: 0246

Selectively Targeting TRBV11-2+ T Cells in Multisystem Inflammatory Syndrome in Children (MIS-C) Using Bispecific T Cell-Engaging Antibodies

Elana Shaw, Stephanie Glavaris, Brian Mog, Alexander Pearlman, Sarah DiNapoli, Jin Liu, Kyle J. Kaeo, Kenneth W. Kinzler, Chetan Bettegowda, Shibin Zhou, Bert Vogelstein, Suman Paul and Maximilian F. Konig, The Johns Hopkins University School of Medicine, Baltimore, MD

Meeting: ACR Convergence 2024

Keywords: COVID-19, cytokines, Inflammation, Miscellaneous Rheumatic and Inflammatory Diseases, T Cell

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Session Information

Date: Saturday, November 16, 2024

Title: Infection-related Rheumatic Disease Poster

Session Type: Poster Session A

Session Time: 10:30AM-12:30PM

Background/Purpose: Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare but potentially deadly immune complication after infection with SARS-CoV-2. In patients with MIS-C, a striking clonal expansion of T cells using the β-chain variable (TRBV) gene 11-2 (TRBV11-2) is observed and correlates with disease severity and cytokine levels. A superantigen (Sag)-like motif adjacent to the furin-like cleavage site (FCS) in the SARS-CoV-2 spike protein (T678NSPRRARSV687) has been implicated as a potential driver of TRBV11-2+ T cell expansion and hyperinflammation. The treatment for MIS-C involves global immunosuppression, but leaves children vulnerable to infections. Ideal treatments for MIS-C would selectively and rapidly eliminate disease-causing, clonally expanding T cells while sparing protective immune responses. Targeting these T cells through their shared germline encoded regions of the T cell receptor (TCR) provides an opportunity to selectively deplete expanded, TRBV11-2+ T cells. We therefore developed a bispecific T cell engaging antibody (BiTE) therapy that eliminates TRBV11-2+ T cells.

Methods: Anti-TRBV11-2 and anti-CD3 single-chain variable fragment (scFv) sequences were synthesized and cloned into mammalian expression vectors. TRBV11-2xCD3 bispecific T-cell engagers (BiTEs) were expressed in ExpiCHO cells. Polyclonal human T cells were CRISPR-Cas12a-edited to remove or replace their endogenous TCRs with 5 disease-associated TRBV11-2+ TCR sequences cloned from patients with MIS-C. Binding of anti-TRBV11-2 to engineered TRBV11-2+ T cells and T cells expressing other TRBV genes was determined by flow cytometry. Engineered MIS-C-derived TRBV11-2+ T cells were stained with CellTrace Violet, incubated with purified spike protein trimers (with or without FCS mutation) or CD3/CD28 T cell activator (positive control), and proliferation measured by flow cytometry. Engineered MIS-C-derived TRBV11-2+ T cells and polyclonal human T cells were treated with TRBV11-2xCD3 BiTEs and depletion of TRBV11-2+ T cells quantified by flow cytometry.

Results: We developed BiTEs to redirect T cells to selectively eliminate TRBV11-2+ T cells that are associated with hyperinflammation in MIS-C (A-B). Anti-TRBV11-2 selectively bound CRISPR-engineered human T cells expressing disease-associated TRBV11-2+ TCRs cloned from patients with MIS-C (C), but not T cells expressing other TRBV alleles or no TCR. Incubation of engineered MIS-C-derived TRBV11-2+ T cells with intact or FCS-mutant spike protein trimers did not result in TRBV11-2+ T-cell proliferation above background, suggesting that the SAg motif alone is insufficient to explain the clonal expansion of TRBV11-2+ T cells in MIS-C. In culture of engineered and polyclonal T cells, TRBV11-2xCD3 BiTEs selectively depleted TRBV11-2+ T cells in a dose-dependent manner (D).

Conclusion: We describe an off-the-shelf, precision immunotherapy approach for the fast and deep depletion of TRBV11-2+ T cells in patients with MIS-C. TRBV11-2xCD3 BiTEs are highly potent and specific at eliminating TRBV11-2+ T cells. TRBV11-2xCD3 BiTEs highlight the opportunities for TCR allele-targeted precision drugs for the treatment of autoimmune and T cell-mediated diseases.

Supporting image 1


Disclosures: E. Shaw: None; S. Glavaris: None; B. Mog: None; A. Pearlman: None; S. DiNapoli: None; J. Liu: None; K. Kaeo: None; K. Kinzler: CAGE Pharma, 8, Clasp, 2, 8, 10, Exact Sciences, 8, Haystack Oncology, 8, 10, Neophore, 2, 8, Personal Genome Diagnostics, 2, 8, Thrive Earlier Detection, 2, 8, 10; C. Bettegowda: Belay Diagnostics, 8, Bionaut Labs, 2, Depuy-Synthes, 2, Haystack Oncology, 2, OrisDx, 8, Privo Technologies, 2; S. Zhou: BioMed Valley Discoveries, 5, Clasp, 2, 8, 10, Exact Sciences, 8, Neophore, 2, 8, Personal Genome Diagnostics, 2, 8; B. Vogelstein: Catalio Capital Management, 2, Clasp Therapeutics, 2, 8, 10, Haystack Oncology, 2, 8, 10, Thrive Earlier Detection, 2, 8, 10; S. Paul: Clasp, 9, 10, Curio Science, 2, IQVIA, 2, Merck, 2; M. Konig: Argenx, 2, Atara Biotherapeutics, 2, ManaT Bio (Clasp), 9, Revel Pharmaceuticals, 2, Sana Biotechnology, 1, 2, Sanofi, 2.

To cite this abstract in AMA style:

Shaw E, Glavaris S, Mog B, Pearlman A, DiNapoli S, Liu J, Kaeo K, Kinzler K, Bettegowda C, Zhou S, Vogelstein B, Paul S, Konig M. Selectively Targeting TRBV11-2+ T Cells in Multisystem Inflammatory Syndrome in Children (MIS-C) Using Bispecific T Cell-Engaging Antibodies [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/selectively-targeting-trbv11-2-t-cells-in-multisystem-inflammatory-syndrome-in-children-mis-c-using-bispecific-t-cell-engaging-antibodies/. Accessed .
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