A Modular Antibody‐Oligomer T Cell Engager for Applications in Local Therapies

Abstract Immunotherapeutics, such as bispecific T cell engagers (BiTEs), have shown promise in cancer therapies, however their efficacy against solid tumors is hindered by transport barriers. Local therapies are being investigated to improve solid tumor immunotherapies and minimize systemic toxicity. Because local therapies bypass the circulatory system, drug properties can be optimized to further enhance local efficacy. Herein, the use of a larger BiTE‐like antibody‐oligomer conjugate is investigated, modular T cell engagers (MoTEs), to extend the duration of activity within local tissue mimics. Specifically, an anti‐CD3 antibody is modified with heterobifunctional ethylene oxide ((EO) 4‐12 ) linkers, which are subsequently modified with cancer targeting ligands (CTLs). The (EO) x molecular weight and CTL grafting densities are optimized to achieve targeted cytotoxicity within in vitro co‐cultures against prostate‐specific membrane antigen (PSMA) positive and human epidermal growth factor receptor 2 (HER2) positive cancer cells. In local tissue models comprised of embedded PSMA positive spheroids in collagen‐hyaluronic acid hydrogels with T cells, it is demonstrated that MoTEs resulted in ≈2.5‐fold greater cytotoxicity toward cancer spheroids than a PSMA targeting BiTE at longer 12‐day timepoints. MoTEsmay therefore prove beneficial for local therapies by extending the duration of action after single‐dose administration and establishing simple synthetic protocols to target various cancer antigens.