T-cell engaging antibodies against new tumor-associated targets

Antibodies provide valuable tools for targeted cancer therapy and can be equipped with artificial effector functions to enhance their therapeutic efficacies. One such effector function is the redirection of T-cell cytotoxicity toward cancer cells which can be achieved by generating a bispecific T-cell engaging antibody (bTCE) that simultaneously binds a tumor-cell target and the T-cell surface molecule CD3. Whereas the mechanism of action of bTCEs is clinically validated, the availability of highly selective tumor-associated targets remains limited. In this study, we investigated antibodies against new tumor-targets for their potential to be used as bTCEs.
First, we generated a modular bTCE-format by adjusting a chemo-enzymatic conjugation method, combining sortase-transpeptidation with click-chemistry to couple CD3-binding fragments to a tumor-targeting antibody. Using this format, we then studied a bTCE based on an antibody, AT1413, that originates from a B-cell of an acute myeloid leukemia (AML) patient and binds a differentially glycosylated variant of CD43 (CD43s). The AT1413 bTCE showed efficacy against AML in vitro and in vivo. Besides AML, AT1413 demonstrated binding also to solid tumor types, including melanoma and mamma carcinoma, and the AT1413 bTCE induced melanoma cell lysis.
Peptides derived from tumor-associated intracellular proteins presented on major histocompatibility complexes (pMHC) provide another type of tumor-target. Combining rabbit-immunization with B-cell immortalization, we generated diverse antibody panels against two pMHC-targets and observed specific tumor-cell lysis for a selected antibody candidate in a bTCE-format.
Results of this study show that CD43s has potential as a bTCE-target and that cancer patient-derived and pMHC-targeting antibodies provide interesting candidates for bTCE-generation.