PD-L1-dependent 4-1BB costimulation enhances anti-tumor efficacy and T cell persistence as monotherapy or in combination with tarlatamab

Bispecific T-cell engagers (TCEs) have demonstrated transformative clinical efficacy by redirecting T cells to eliminate tumor cells. However, clinical outcomes highlight opportunities to further enhance therapeutic benefits, particularly by improving overall response rates and durability of responses. Sustained CD3 engagement by TCEs can lead to T cell exhaustion, resulting in diminished effector function and reduced persistence. To address these challenges, we developed AMG 728, a PD-L1-targeted 4-1BB bispecific molecule designed to enhance T cell anti-tumor activity and persistence. AMG 728 simultaneously blocks PD-1/PD-L1 inhibitory signaling and activates 4-1BB costimulatory signaling in a PD-L1-dependent manner. This dual mechanism is intended to enhance T cell activation and persistence while minimizing the risk of immune activation and off-tumor toxicity associated with systemic 4-1BB agonism. By combining the CD3-mediated signaling from TCEs with 4-1BB costimulation provided by AMG 728, we aimed to fully activate T cells, thereby promoting cytolytic effector differentiation, improving survival, and expanding memory T cell populations. A mouse surrogate PD-L1-4-1BB bispecific molecule demonstrated dose-dependent anti-tumor efficacy as a monotherapy in a human PD-L1/4-1BB double knock-in mouse model bearing syngeneic, human PD-L1-expressing tumors. Mechanistic characterization of this surrogate molecule further revealed several potential pharmacodynamic biomarkers in vivo , including increased CD8 + T cell proliferation, expansion of central memory T cells in draining lymph nodes, enhanced cytolytic effector T cell differentiation within tumors, and elevated levels of soluble 4-1BB. Furthermore, AMG 728 was evaluated for its potential to improve the efficacy of tarlatamab, a DLL3-targeted bispecific TCE in vitro and in a T cell humanized small cell lung cancer (SCLC) preclinical mouse model. Selective 4-1BB agonism on PD-L1-positive tumors enhanced the cytotoxic activity of tarlatamab in vitro . In the human PD-L1-overexpressing SHP-77 SCLC xenograft implanted in NSG mice, combination treatment with AMG 728 and tarlatamab at suboptimal doses resulted in significantly greater tumor growth inhibition, extended survival, and a higher frequency of complete responses, compared with either monotherapy. Notably, AMG 728 treatment led to a significant increase in central memory T cells in the tumors from tarlatamab-treated mice. Collectively, these findings suggest that the addition of AMG 728 to tarlatamab represents a rational combination strategy that enhances T cell activation and longevity, resulting in improved antitumor activity and survival.