Enhancing Cancer Immunotherapy: The Development and Potential of ATOR-1017

4-1BB, or CD137, is a co-stimulatory receptor found on activated T-cells and NK cells, and its activation can lead to tumor eradication and long-term immunity in various experimental models. However, clinical development of 4-1BB antibodies has been hindered by toxic side effects and limited efficacy.

ATOR-1017 is a novel anti-4-1BB IgG4 antibody that targets a unique 4-1BB epitope in domain 2, blocking ligand binding and requiring Fcγ Receptor (FcγR) I and IIb crosslinking for its agonistic effect. This design may contribute to a more favorable safety profile, as evidenced by the absence of immunotoxicity in cytokine release assays using human peripheral blood mononuclear cells (PBMCs).

Expression analysis shows that 4-1BB and FcγRs are predominantly expressed in the tumor microenvironment, with minimal co-expression in non-tumor tissues like the liver, suggesting that ATOR-1017 could induce localized immune activation with reduced systemic adverse effects. A pilot toxicology study in cynomolgus monkeys, which demonstrated no clinical signs at any administered dose, supports this safety profile.

ATOR-1017's design, preclinical data, and pilot toxicology study indicate a promising balance of safety and efficacy, with a dependency on FcγR-mediated crosslinking, a clean cytokine release profile, and no observed clinical adverse events. The antibody is currently in preclinical development, with plans to initiate a phase I clinical trial in 2019.