Abstract A183: ATOR-1017: A 4-1BB antibody designed for superior safety/efficacy profile in cancer immunotherapy

Abstract

4-1BB (CD137) is an inducible co-stimulatory receptor expressed on activated T-cells and natural killer (NK) cells. Activation of 4-1BB induces proliferation, cytokine production, cytotoxic function and survival of T and NK cells. Most importantly, it has been shown to result in tumor eradication and long-term tumor immunity in numerous experimental tumor models. Thus, 4-1BB agonists may have great potential in cancer immunotherapy. However, the 4-1BB antibodies in clinical development are associated with toxic side effects and/or poor efficacy, potentially limiting their clinical use. ATOR-1017 is an anti-4-1BB IgG4 antibody designed to overcome the limitations observed with other 4-1BB antibodies. It binds to a distinct 4-1BB epitope located in domain 2 and blocks 4-1BB ligand binding. Furthermore, its agonistic effect is dependent on crosslinking by Fcγ Receptor (FcγR) I and IIb. A potentially advantageous safety profile was supported by the lack of observed immunotoxicity in a cytokine release assay based on human PBMC using a panel of proinflammatory cytokines as readout. Furthermore, expression profiling of human tumor and normal tissue demonstrates that 4-1BB and FcγRs are highly expressed in the tumor environment. In contrast, co-expression of 4-1BB and FcγRs in non-tumor tissues, such as the liver, is low. Therefore, ATOR-1017 is expected to result in tumor-localized immune activation, thereby avoiding systemic adverse events, including hepatotoxicity, which has been observed by another, FcγR-independent 4-1BB antibody. Finally, to further investigate the safety profile of ATOR-1017, a pilot toxicology study was conducted. ATOR-1017 binds with similar affinity of approximately 0.2 nM to human and cynomolgus monkey 4-1BB, whereas no detectable binding to mouse 4-1BB is observed. Thus, cynomolgus monkeys were administered four weekly doses of 5, 15 or 50 mg/kg ATOR-1017. No clinical signs were observed at any dose, indicating a favorable safety profile. In conclusion, ATOR-1017 was designed to be highly active in the tumor environment, and to have minimal systemic effects, thereby enabling a superior safety/efficacy profile. This is supported by a preclinical data package, demonstrating dependency on FcγR-mediated crosslinking, a clean profile in cytokine release assay, 4-1BB and FcγRs co-expression in the tumor and no clinical adverse events observed in a repeat dosing pilot toxicology study. ATOR-1017 is in preclinical development with initiation of phase I anticipated in 2019. Citation Format: Eva Dahlen, Anna Rosen, Karin Barchan, Anna Dahlman, Peter Ellmark, Tina Furebring, Karin Enell Smith. ATOR-1017: A 4-1BB antibody designed for superior safety/efficacy profile in cancer immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A183.