Nature cancer · 2025
TRBC2-targeting antibody-drug conjugates for the treatment of T cell cancers.
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Ge Jiaxin, Urban Joshua, DiNapoli Sarah R, Lee Bum Seok, Ahmedna Taha, Nichakawade Tushar D, Mog Brian J, Lu Steve, Li Xuyang, Marcou Nikita, Glavaris Stephanie, Douglass Jacqueline, Liu Jin, Konig Maximilian F, Watson Evangeline, Popoli Maria, Peske J David, Rozati Sima, Sterling Cole H, Wagner-Johnston Nina, Ambinder Richard F, Gabrielson Kathy, Mullighan Charles G, Papadopoulos Nickolas, Bettegowda Chetan, Pardoll Drew M, Zhou Shibin, Sur Surojit, Kinzler Kenneth W, Vogelstein Bert, Paul Suman
Аннотация
Antibody-drug conjugates (ADCs) have been remarkably successful in treating solid and hematological malignancies. Generation of ADCs for T cell cancers is challenging because the ADCs must selectively target cancerous T cells while sparing some normal T cells necessary for immune function. T cells express one of two TRBC alleles: TRBC1 or TRBC2. Normal T cells are composed of about 40% TRBC1-expressing and 60% TRBC2-expressing cells. In contrast, T cell malignancies are characterized by the clonal expression of either TRBC1 or TRBC2. Selective targeting of TRBC1 or TRBC2 enables the killing of cancer cells but preserves about 60-40% of the normal T cells. To enable such a therapy for cancers expressing TRBC2, here we developed a high-affinity anti-TRBC2 antibody. An ADC generated with this antibody and a pyrrolobenzodiazepine dimer payload showed specific killing of TRBC2+ cancers in vitro and in mouse models. The anti-TRBC2 ADC provides a promising, off-the-shelf therapy for patients with T cell cancers.