Antibody therapeutics · 2026
DOTAM-TCB: Universal Small Molecule-guided Hapten- and T Cell-bispecific Antibodies for Cancer Immunotherapy.
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Surowka Marlena, Kober Theresa, Matscheko Daniela, Ehler Andreas, Macedo Wilson, Assisi Denis, Challier John, Sobieniecki Andrzej, Gianotti Reto, Bransi Ali, Sam Johannes, Bonfiglio Juan José, Wichert Moreno, Ricci Antonio, Benz Joerg, Umaña Pablo, Venetz Dario, Klein Christian
Аннотация
BACKGROUND: Tumor heterogeneity has been identified as a major roadblock for cancer immunotherapy. To overcome this, universal effector cell engagers with interchangeable tumor-targeting adaptors have been developed. Current concepts in this field consist of antibody-based adaptors. Small-molecule (SM) ligands, on the other hand, infiltrate tissues rapidly, have short half-lives, and are potentially orally available. Therefore, we hypothesized that utilizing SM adaptors, combined with effector antibodies, could represent an attractive off-the-shelf therapy.
METHODS: Here, we introduce the development of target-agnostic, small-molecule-guided hapten- and T cell-bispecific (TCB) antibodies with high affinity between the adaptor-effector pair. Specifically, we designed SM adaptors based on known tumor-targeting ligands with specificity to the antigens folate receptor 1 (FOLR1), prostate-specific membrane antigen (PSMA) and carbonic anhydrase IX (CAIX), and conjugated them to Ca2+-loaded 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (DOTAM) as a hapten. As an effector antibody, we designed DOTAM-specific T cell bispecific antibodies (DOTAM-TCB) with femtomolar (fM) affinity for the hapten.
RESULTS: In vitro experiments showed in-solution assembly of stable adaptor-effector complexes. Additionally, T cell-mediated tumor killing was initiated by the universal DOTAM-TCB when combined with adaptors across various tumor cells. Ex vivo study of CAIX-directed Ca-DOTAM-acetazolamide (Ca-DOTAM-AAZ) with DOTAM-TCB showed potent activation of T cells against murine-engrafted human HT-29 tumor.
CONCLUSIONS: The studies described here demonstrate proof-of-concept for using hapten-containing small molecules as adaptors for effective universal T cell engager-based cancer immunotherapy.
METHODS: Here, we introduce the development of target-agnostic, small-molecule-guided hapten- and T cell-bispecific (TCB) antibodies with high affinity between the adaptor-effector pair. Specifically, we designed SM adaptors based on known tumor-targeting ligands with specificity to the antigens folate receptor 1 (FOLR1), prostate-specific membrane antigen (PSMA) and carbonic anhydrase IX (CAIX), and conjugated them to Ca2+-loaded 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (DOTAM) as a hapten. As an effector antibody, we designed DOTAM-specific T cell bispecific antibodies (DOTAM-TCB) with femtomolar (fM) affinity for the hapten.
RESULTS: In vitro experiments showed in-solution assembly of stable adaptor-effector complexes. Additionally, T cell-mediated tumor killing was initiated by the universal DOTAM-TCB when combined with adaptors across various tumor cells. Ex vivo study of CAIX-directed Ca-DOTAM-acetazolamide (Ca-DOTAM-AAZ) with DOTAM-TCB showed potent activation of T cells against murine-engrafted human HT-29 tumor.
CONCLUSIONS: The studies described here demonstrate proof-of-concept for using hapten-containing small molecules as adaptors for effective universal T cell engager-based cancer immunotherapy.