Targeting poorly differentiated thyroid cancer with bispecific antibodies and CAR T cells from the human anti-TSHR autoantibody repertoire
- 1Laboratory of Translational Immuno-Oncology, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland
Abstract
Background: Poorly differentiated thyroid carcinoma (PDTC) has no effective systemic treatment option once radioactive iodine and tyrosine kinase inhibitors fail. The thyroid-stimulating hormone receptor (TSHR) is highly tissue-restricted and the anti-TSHR autoantibody repertoire of thyroid autoimmunity offers sequence-defined, fully human binders. We asked whether this repertoire can be converted into an off-the-shelf T cell-redirecting therapy for PDTC. Methods: TSHR expression was profiled on a 151-case thyroid cancer tissue microarray (TMA), 50 healthy controls and on fresh tumor material. Eight anti-TSHR clones, four of human autoimmune origin (M22, K1-18, K1-70, 5C9) and four murine (IRI-SAb2, IRI-SAb3, 9D33, 1H7), were reformatted as CD3-engaging bispecific antibodies (bsAbs; anti-TSHR Fab x anti-CD3 scFv) and, for leading clones, as chimeric antigen receptor (CAR) T cells. Activity was compared in vitro, across graded and mixed antigen densities and in a CAL-62-Luc-TSHR xenograft model, using healthy-donor (HD) or thyroid cancer-patient T cells. Results: TSHR was retained on a substantial fraction of PDTC, including metastatic lesions. Both formats mediated potent, antigen-selective killing and the leading bsAbs suppressed xenograft growth in vivo. For CAR T cells, scFv heavy/light-chain orientation was decisive. Anti-TSHR bsAbs cleared mixed cultures far beyond the antigen-positive fraction matching mosunetuzumab and indicating a modality-intrinsic bystander effect. Patient-derived T cells obtained on or after oncological treatment retained full effector function. Conclusions: The anti-TSHR autoantibody repertoire provides a promising source of binders for off-the-shelf bispecific antibodies targeting TSHR-positive thyroid cancer, while CAR T cells offer an autologous alternative.
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BibTeX
@misc{fischer2026targeting,
title = {{Targeting poorly differentiated thyroid cancer with bispecific antibodies and CAR T cells from the human anti-TSHR autoantibody repertoire}},
author = {C. Fischer and A. Eugster and B. Besemer and M. Buchi and M. Bauer and C. Schultheiss and E. D'Arcangelo and F. Filipsky and C. Wickenhauser and A. Wilfer and K. Lorenz and J. Jakscha and L. Muller and R. Köberle-Wührer and B. Kasenda and C. Rottenburger and R. Latif and T. F. Davies and H. Läubli and M. Peipp and M. Binder},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.19.760040},
url = {https://www.biorxiv.org/content/10.64898/2026.10.19.760040v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Targeting poorly differentiated thyroid cancer with bispecific antibodies and CAR T cells from the human anti-TSHR autoantibody repertoire
AU - C. Fischer
AU - A. Eugster
AU - B. Besemer
AU - M. Buchi
AU - M. Bauer
AU - C. Schultheiss
AU - E. D'Arcangelo
AU - F. Filipsky
AU - C. Wickenhauser
AU - A. Wilfer
AU - K. Lorenz
AU - J. Jakscha
AU - L. Muller
AU - R. Köberle-Wührer
AU - B. Kasenda
AU - C. Rottenburger
AU - R. Latif
AU - T. F. Davies
AU - H. Läubli
AU - M. Peipp
AU - M. Binder
PY - 2026
DA - 2026/10/19
PB - bioRxiv
DO - 10.64898/2026.10.19.760040
UR - https://www.biorxiv.org/content/10.64898/2026.10.19.760040v1
AB - Background: Poorly differentiated thyroid carcinoma (PDTC) has no effective systemic treatment option once radioactive iodine and tyrosine kinase inhibitors fail. The thyroid-stimulating hormone receptor (TSHR) is highly tissue-restricted and the anti-TSHR autoantibody repertoire of thyroid autoimmunity offers sequence-defined, fully human binders. We asked whether this repertoire can be converted into an off-the-shelf T cell-redirecting therapy for PDTC. Methods: TSHR expression was profiled on a 151-case thyroid cancer tissue microarray (TMA), 50 healthy controls and on fresh tumor material. Eight anti-TSHR clones, four of human autoimmune origin (M22, K1-18, K1-70, 5C9) and four murine (IRI-SAb2, IRI-SAb3, 9D33, 1H7), were reformatted as CD3-engaging bispecific antibodies (bsAbs; anti-TSHR Fab x anti-CD3 scFv) and, for leading clones, as chimeric antigen receptor (CAR) T cells. Activity was compared in vitro, across graded and mixed antigen densities and in a CAL-62-Luc-TSHR xenograft model, using healthy-donor (HD) or thyroid cancer-patient T cells. Results: TSHR was retained on a substantial fraction of PDTC, including metastatic lesions. Both formats mediated potent, antigen-selective killing and the leading bsAbs suppressed xenograft growth in vivo. For CAR T cells, scFv heavy/light-chain orientation was decisive. Anti-TSHR bsAbs cleared mixed cultures far beyond the antigen-positive fraction matching mosunetuzumab and indicating a modality-intrinsic bystander effect. Patient-derived T cells obtained on or after oncological treatment retained full effector function. Conclusions: The anti-TSHR autoantibody repertoire provides a promising source of binders for off-the-shelf bispecific antibodies targeting TSHR-positive thyroid cancer, while CAR T cells offer an autologous alternative.
ER -