FS222 mAb2: A CD137 and PD-L1 Dual-Targeting Agent for Enhanced Lymphocyte Activation and Safety

The PD-1/L1 immune checkpoint blockade has been shown to provide long-term responses and extend the survival of certain cancer patients. Clinical trials are currently exploring the use of Tumor Necrosis Factor Receptor (TNFR) activation to enhance patient outcomes. However, the effectiveness of monoclonal antibodies (mAbs) in clinical settings is often hindered by the low affinity of FcΓR-mediated crosslinking and the associated safety risks. A novel bispecific agonist targeting CD137 has been developed with the aim of expanding the therapeutic window. This bispecific antibody, referred to as FS222, incorporates a CD137-binding specificity into the Fc-region of a human IgG1 monoclonal antibody that also targets PD-L1. The introduction of a LALA mutation significantly diminishes FcΓR binding. The binding characteristics of FS222 were evaluated using surface plasmon resonance (SPR) and cell binding assays, while its in vitro activity was measured through human primary T cell assays. A study in cynomolgus monkeys was conducted to examine toxicity, pharmacokinetics (PK), and pharmacodynamics (PD). Additionally, a murine surrogate molecule was created to test anti-tumor activity and PK/PD in various syngeneic mouse tumor models.

FS222 exhibits subnanomolar affinity for human PD-L1, which is essential for its conditional agonism mechanism, enabling highly potent CD137 agonism in primary cell in vitro assays. In cynomolgus monkeys, FS222 demonstrated a half-life of approximately 150 hours, and both single and repeated dosing led to observable PD changes in lymphocytes and soluble receptor levels at low doses. Importantly, no hepatotoxicity was detected. The surrogate anti-mouse-mAb2 significantly reduced tumor growth in multiple syngeneic mouse tumor models, with dose-dependent tumor growth inhibition correlating with increased survival and enhanced tumor and peripheral activated CD8+ T cells.

FS222 has demonstrated superior activity compared to control mAbs and relevant combinations in in vitro assays. It also showed a favorable safety profile and immunopharmacological effects in the cynomolgus monkey study and with the surrogate molecule in syngeneic mouse tumor models. Despite clinical development of anti-CD137 agonistic mAbs facing limitations due to dose-limiting toxicity or poor clinical activity, preclinical tumor models have shown that treatment with the anti-CD137/PD-L1 surrogate mAb2 leads to intra-tumoral and peripheral PD changes, resulting in increased CD8+ T cell proliferation. These effects are dose-dependent and coincide with tumor growth inhibition. FS222 is a highly active bispecific molecule with a promising safety profile, indicating its potential to address significant unmet needs in the immunotherapy of solid tumors.