FTL008.16, a 5T4-Conditional 4-1BB bispecific antibody, potently enhances antitumor immunity via tumor-directed...

The clinical development of 4-1BB agonists for cancer immunotherapy has been constrained by dose-limiting toxicities, particularly hepatotoxicity. To overcome this challenge, we developed FTL008.16, a novel bispecific antibody targeting 4-1BB (CD137) on T cells and the tumor-associated antigen 5T4. FTL008.16 is a human IgG1 antibody bearing an effector-deficient Fc region that specifically binds 4-1BB at an epitope overlapping with that of its natural ligand (4-1BBL), potentially mimicking physiological 4-1BBL-mediated co-stimulation. As demonstrated through in vitro reporter assays and primary cell-based systems, FTL008.16 elicits dose-dependent 4-1BB activation strictly contingent on 5T4 engagement, enhancing T-cell proliferation, cytokine secretion, and tumor cell lysis, thereby demonstrating potent antitumor efficacy in preclinical models. In vivo, FTL008.16 exhibited superior efficacy over a conventional anti-4-1BB monoclonal antibody, suppressing established tumors in both CT26 and MC38 models, with complete regression observed in CT26 tumors. In cynomolgus monkeys, FTL008.16 demonstrated an excellent safety profile, with no elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) observed even at 50 mg/kg. Importantly, this 5T4-restricted activation mechanism confines immune stimulation to the tumor microenvironment, thereby circumventing the systemic toxicity associated with conventional 4-1BB agonists. Collectively, these findings establish FTL008.16 as a conditionally active immunotherapeutic agent that successfully achieves both robust antitumor efficacy and a favorable safety profile.