Researchers at the Johns Hopkins Kimmel Cancer Center's Ludwig Center have developed a new antibody-drug conjugate therapy that targets TRBC2-positive T-cell cancers. This approach builds on their previous work from 2024, which focused on TRBC1-positive tumors.
The new therapy uses an antibody to target a specific protein found on the surface of T-cell cancers and delivers a drug designed to kill cancer cells. The findings were published in Nature Cancer on December 22.
T-cell lymphomas and leukemias affect about 100,000 people globally each year. These types of cancers are rare and complex, with fewer treatment options compared to B cell malignancies. Adults with relapsed T-cell cancers face five-year survival rates between 7% and 38%.
"There is a challenging situation," said senior author Suman Paul, M.B.B.S., Ph.D., assistant professor of oncology. "Because unlike B-cell therapies - where eliminating both cancerous and healthy B cells is tolerable - therapies targeting T cells must preserve enough normal T cells for patients to survive infections."
Paul added, "The tricky part is that if the drug kills both the T-cell lymphoma and the normal T cells, then it's very hard for that person to survive. We have to be mindful that it has to get rid of the cancer, but it cannot completely get rid of the normal T cells."
To address this challenge, researchers targeted TRBC1 or TRBC2—two mutually exclusive genetic variants of the T-cell receptor. Normal T cells are composed of roughly 40% TRBC1-positive and 60% TRBC2-positive populations; however, each individual cancer expresses only one variant. By selectively targeting the variant present in cancer cells, approximately 40%–60% of normal T cells can be preserved.
In their latest study, researchers used a phage-displayed antibody library to create JX1.1, an antibody that recognizes only the TRBC2 protein target.
"Our antibody was developed using SLISY, a next-generation sequencing-based platform for rapid identification of antibody candidates from a phage library," said Ken Kinzler, Ph.D., Barry Family Professor in Oncology and director of the Ludwig Center.
The team linked JX1.1 to pyrrolobenzodiazepine—a drug toxic to cancer cells—to form an antibody-drug conjugate (ADC). Laboratory tests using cell lines and animal models showed that this ADC specifically targeted TRBC2-positive cancers while sparing normal TRBC1-positive T cells. The ADC led to strong tumor regression in animal models with minimal toxicity; all treated mice remained free from detectable cancer throughout a follow-up period lasting 150 days.
"The development of TRBC1 and TRBC2 antibodies together now provides a conceptual 'matched set' of precision tools for the great majority of patients with T-cell cancers," Paul said.
Several other researchers contributed to this study: Jiaxin Ge, Joshua Urban, Sarah DiNapoli, Bum Seok Lee, Taha Ahmedna, Tushar Nichakawade, Brian Mog, Steve Lu, Xuyang Li, Nikita Marcou, Stephanie Glavaris, Jacqueline Douglass, Jin Liu, Maximilian Konig, Evangeline Watson, Maria Popoli, J. David Peske, Sima Rozati, Cole Sterling, Nina Wagner-Johnston, Richard Ambinder, Kathy Gabrielson, Charles Mullighan, Nickolas Papadopoulos, Chetan Bettegowda, Drew Pardoll, Shibin Zhou, Surojit Sur,Kenneth Kinzler,and Bert Vogelstein.
Funding for this research came from several organizations including grants from the Virginia and D.K. Ludwig Fund for Cancer Research; Lustgarten Foundation for Pancreatic Cancer Research; Commonwealth Fund; Bloomberg–Kimmel Institute for Cancer Immunotherapy; Bloomberg Philanthropies; National Institutes of Health (NIH) Cancer Center Support Grant P30 CA006973; CA021765; R35 CA197695 NIH grants T32 GM136577 and P30CA51008; National Cancer Institute Grants K08CA270403 and R37 CA230400; National Institute of Allergy and Infectious Diseases grant 1R21AI176764-01; National Institute of General Medical Sciences grant T32GM007057-47; Blood Cancer United (formerly Leukemia & Lymphoma Society); Translation Research Program award; American Society of Hematology Scholar award; Swim Across America/Baltimore Translational Cancer Research award; Jerome Greene Foundation; Cupid Foundation; and American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital.
Several inventors listed in this study—including Ge,Nichakawade ,Li ,Konig ,Papadoulos ,Pardoll ,Zhou ,Kinzler ,Vogelstein,and Paul—are credited as inventors on technologies described in this research.
