To improve on the limited clinical success of CD40- and 4-1BB-agonist Ab monotherapies, Huik and Adams et al. carried out in vitro studies of DuoBody-CD40x4-1BB, a novel dual-targeting Fc-inert bispecific Ab. DuoBody-CD40x4-1BB binding was strictly dependent on crosslinking CD40+ APCs with 4-1BB+ T cells, resulting in increased DC–T cell interactions and DC maturation, and enhanced T cell proliferation and effector function. DuoBody-CD40x4-1BB enhanced TIL expansion ex vivo, and combination with anti-PD-1 amplified the immune response. Patient blood samples from a first-in-human trial revealed confirmatory pharmacodynamic markers.
Contributed by Katherine Turner
BACKGROUND: Despite the preclinical promise of CD40 and 4-1BB as immuno-oncology targets, clinical efforts evaluating CD40 and 4-1BB agonists as monotherapy have found limited success. DuoBody-CD40x4-1BB (GEN1042/BNT312) is a novel investigational Fc-inert bispecific antibody for dual targeting and conditional stimulation of CD40 and 4-1BB to enhance priming and reactivation of tumor-specific immunity in patients with cancer. METHODS: Characterization of DuoBody-CD40x4-1BB in vitro was performed in a broad range of functional immune cell assays, including cell-based reporter assays, T-cell proliferation assays, mixed-lymphocyte reactions and tumor-infiltrating lymphocyte assays, as well as live-cell imaging. The in vivo activity of DuoBody-CD40x4-1BB was assessed in blood samples from patients with advanced solid tumors that were treated with DuoBody-CD40x4-1BB in the dose-escalation phase of the first-in-human clinical trial (NCT04083599). RESULTS: DuoBody-CD40x4-1BB exhibited conditional CD40 and 4-1BB agonist activity that was strictly dependent on crosslinking of both targets. Thereby, DuoBody-CD40x4-1BB strengthened the dendritic cell (DC)/T-cell immunological synapse, induced DC maturation, enhanced T-cell proliferation and effector functions in vitro and enhanced expansion of patient-derived tumor-infiltrating lymphocytes ex vivo. The addition of PD-1 blocking antibodies resulted in potentiation of T-cell activation and effector functions in vitro compared with either monotherapy, providing combination rationale. Furthermore, in a first-in-human clinical trial, DuoBody-CD40x4-1BB mediated clear immune modulation of peripheral antigen presenting cells and T cells in patients with advanced solid tumors. CONCLUSION: DuoBody-CD40_4-1BB is capable of enhancing antitumor immunity by modulating DC and T-cell functions and shows biological activity in patients with advanced solid tumors. These findings demonstrate that targeting of these two pathways with an Fc-inert bispecific antibody may be an efficacious approach to (re)activate tumor-specific immunity and support the clinical investigation of DuoBody-CD40x4-1BB for the treatment of cancer.
Author Info: (1) BioNTech SE, Mainz, Germany. (2) Genmab US Inc, Plainsboro, New Jersey, USA. (3) BioNTech SE, Mainz, Germany. (4) Translational Research and Precision Medicine, Genmab BV, Utre
Author Info: (1) BioNTech SE, Mainz, Germany. (2) Genmab US Inc, Plainsboro, New Jersey, USA. (3) BioNTech SE, Mainz, Germany. (4) Translational Research and Precision Medicine, Genmab BV, Utrecht, The Netherlands. (5) BioNTech SE, Mainz, Germany. (6) Genmab US Inc, Plainsboro, New Jersey, USA. (7) BioNTech SE, Mainz, Germany. (8) Translational Research and Precision Medicine, Genmab BV, Utrecht, The Netherlands. (9) TRON-Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Mainz, Germany. (10) Translational Research and Precision Medicine, Genmab BV, Utrecht, The Netherlands. (11) Genmab US Inc, Plainsboro, New Jersey, USA. (12) TRON-Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Mainz, Germany. (13) BioNTech SE, Mainz, Germany. (14) BioNTech SE, Mainz, Germany. (15) Genmab US Inc, Plainsboro, New Jersey, USA. (16) BioNTech SE, Mainz, Germany. (17) Genmab BV, Utrecht, The Netherlands. (18) BioNTech SE, Mainz, Germany. (19) Experimental Medicine, Genmab US Inc, Plainsboro, New Jersey, USA. (20) Translational Research and Precision Medicine, Genmab BV, Utrecht, The Netherlands. (21) BioNTech SE, Mainz, Germany. (22) Genmab US Inc, Plainsboro, New Jersey, USA. (23) BioNTech SE, Mainz, Germany. TRON-Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Mainz, Germany. (24) Genmab US Inc, Plainsboro, New Jersey, USA mjk@genmab.com.
