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; Suman Paul

doi:10.1038/s41586-024-07233-2

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

Nature. 2024 Apr;628(8007):416-423. doi: 10.1038/s41586-024-07233-2. Epub 2024 Mar 27.

Authors

Tushar D Nichakawade^{1

2

3

4}, Jiaxin Ge^{1

2}, Brian J Mog^{1

2

5}, Bum Seok Lee^{1

2}, Alexander H Pearlman^{1

2}, Michael S Hwang^{1

2

6}, Sarah R DiNapoli^{1

2}, Nicolas Wyhs^{1

2}, Nikita Marcou^{1

2}, Stephanie Glavaris^{1

2}, Maximilian F Konig^{1

2

4

7}, Sandra B Gabelli^{8

9

10}, Evangeline Watson^{1

2}, Cole Sterling¹¹, Nina Wagner-Johnston¹¹, Sima Rozati¹², Lode Swinnen¹¹, Ephraim Fuchs¹¹, Drew M Pardoll^{8

9}, Kathy Gabrielson^{9

13}, Nickolas Papadopoulos^{1

9

13}, Chetan Bettegowda^{1

14}, Kenneth W Kinzler^{1

8

9}, Shibin Zhou^{1

8

9}, Surojit Sur^{1

2

9}, Bert Vogelstein^{1

2

8

9

13}, Suman Paul^{15

16}

Affiliations

¹ Ludwig Center and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Howard Hughes Medical Institute, Chevy Chase, MD, USA.
³ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁴ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
⁵ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁶ Genentech, San Francisco, CA, USA.
⁷ Division of Rheumatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
⁹ Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹⁰ Discovery Chemistry, Merck Research Laboratory, Merck and Co, West Point, PA, USA.
¹¹ Division of Hematologic Malignancies and Bone Marrow Transplantation, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹² Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹³ Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹⁴ Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁵ Ludwig Center and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. spaul19@jhmi.edu.
¹⁶ Division of Hematologic Malignancies and Bone Marrow Transplantation, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA. spaul19@jhmi.edu.

PMID: 38538786
DOI: 10.1038/s41586-024-07233-2

Abstract

Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies^1-9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival^10,11 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 cells^13,14. 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.

MeSH terms

Animals
Female
Humans
Immunoconjugates* / immunology
Immunoconjugates* / therapeutic use
Immunotherapy, Adoptive
Leukemia, T-Cell* / drug therapy
Leukemia, T-Cell* / immunology
Lymphoma, T-Cell* / drug therapy
Lymphoma, T-Cell* / immunology
Mice
Receptors, Antigen, T-Cell, alpha-beta* / immunology
Receptors, Chimeric Antigen / immunology
T-Lymphocytes* / immunology
Xenograft Model Antitumor Assays

Substances

Immunoconjugates
Receptors, Antigen, T-Cell, alpha-beta
Receptors, Chimeric Antigen
TRBC1 protein, human

Grants and funding

K08 CA270403/CA/NCI NIH HHS/United States