TRBC1-targeting antibody–drug conjugates for the treatment of T cell cancers

Tushar D. Nichakawade, Jiaxin Ge, Brian J. Mog, Bum Seok Lee, Alexander H. Pearlman, Michael S. Hwang, Sarah R. DiNapoli, Nicolas Wyhs, Nikita Marcou, Stephanie Glavaris, Maximilian F. Konig, Sandra B. Gabelli, Evangeline Watson, Cole Sterling, Nina Wagner-Johnston, Sima Rozati, Lode Swinnen, Ephraim Fuchs, Drew M. Pardoll, Kathy Gabrielson, Nickolas Papadopoulos, Chetan Bettegowda, Kenneth W. Kinzler, Shibin Zhou, Surojit Sur, Bert Vogelstein and Suman Paul ()
Additional contact information
Tushar D. Nichakawade: The Johns Hopkins University School of Medicine
Jiaxin Ge: The Johns Hopkins University School of Medicine
Brian J. Mog: The Johns Hopkins University School of Medicine
Bum Seok Lee: The Johns Hopkins University School of Medicine
Alexander H. Pearlman: The Johns Hopkins University School of Medicine
Michael S. Hwang: The Johns Hopkins University School of Medicine
Sarah R. DiNapoli: The Johns Hopkins University School of Medicine
Nicolas Wyhs: The Johns Hopkins University School of Medicine
Nikita Marcou: The Johns Hopkins University School of Medicine
Stephanie Glavaris: The Johns Hopkins University School of Medicine
Maximilian F. Konig: The Johns Hopkins University School of Medicine
Sandra B. Gabelli: Sidney Kimmel Comprehensive Cancer Center
Evangeline Watson: The Johns Hopkins University School of Medicine
Cole Sterling: Johns Hopkins School of Medicine
Nina Wagner-Johnston: Johns Hopkins School of Medicine
Sima Rozati: Johns Hopkins School of Medicine
Lode Swinnen: Johns Hopkins School of Medicine
Ephraim Fuchs: Johns Hopkins School of Medicine
Drew M. Pardoll: Sidney Kimmel Comprehensive Cancer Center
Kathy Gabrielson: Johns Hopkins School of Medicine
Nickolas Papadopoulos: The Johns Hopkins University School of Medicine
Chetan Bettegowda: The Johns Hopkins University School of Medicine
Kenneth W. Kinzler: The Johns Hopkins University School of Medicine
Shibin Zhou: The Johns Hopkins University School of Medicine
Surojit Sur: The Johns Hopkins University School of Medicine
Bert Vogelstein: The Johns Hopkins University School of Medicine
Suman Paul: The Johns Hopkins University School of Medicine

Nature, 2024, vol. 628, issue 8007, 416-423

Abstract: Abstract Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies1–9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival10,11 and lack such targeted therapies. Thus, T cell cancers particularly warrant the development of CAR T cells and antibodies to improve patient outcomes. Preclinical studies showed that targeting T cell receptor β-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity12, making TRBC1 an attractive target to treat T cell cancers. However, the first-in-human clinical trial of anti-TRBC1 CAR T cells reported a low response rate and unexplained loss of anti-TRBC1 CAR T cells13,14. Here we demonstrate that CAR T cells are lost due to killing by the patient’s normal T cells, reducing their efficacy. To circumvent this issue, we developed an antibody–drug conjugate that could kill TRBC1+ cancer cells in vitro and cure human T cell cancers in mouse models. The anti-TRBC1 antibody–drug conjugate may provide an optimal format for TRBC1 targeting and produce superior responses in patients with T cell cancers.

Date: 2024
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41586-024-07233-2 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:628:y:2024:i:8007:d:10.1038_s41586-024-07233-2

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-07233-2

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().