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Updated: Sep 20, 2025
Generation of Human CD40-activated B cells
Published on: October 16, 2009
DuoBody-CD40x4-1BB induces dendritic-cell maturation and enhances T-cell activation through conditional CD40 and
Alexander Muik1, Homer C Adams 3rd2, Friederike Gieseke1
1BioNTech SE, Mainz, Germany.
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-CD40×4-1BB (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-CD40×4-1BB 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-CD40×4-1BB was assessed in blood samples from patients with advanced solid tumors that were treated with DuoBody-CD40×4-1BB in the dose-escalation phase of the first-in-human clinical trial (NCT04083599).
Results:
DuoBody-CD40×4-1BB exhibited conditional CD40 and 4-1BB agonist activity that was strictly dependent on crosslinking of both targets. Thereby, DuoBody-CD40×4-1BB 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-CD40×4-1BB 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-CD40×4-1BB for the treatment of cancer.
Insights
DuoBody-CD40×4-1BB, a bispecific antibody, conditionally stimulates CD40 and 4-1BB to enhance anti-tumor immunity. This novel approach shows biological activity in patients with advanced solid tumors, supporting its clinical investigation.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- CD40 and 4-1BB agonists show preclinical promise in immuno-oncology but limited clinical success as monotherapy.
- DuoBody-CD40×4-1BB is an investigational Fc-inert bispecific antibody designed for dual targeting and conditional stimulation of CD40 and 4-1BB.
- The antibody aims to enhance priming and reactivation of tumor-specific immunity in cancer patients.
Purpose of the Study:
- To characterize the in vitro and in vivo activity of DuoBody-CD40×4-1BB.
- To evaluate its potential to enhance anti-tumor immunity.
- To support its clinical investigation in cancer treatment.
Main Methods:
- In vitro characterization using various immune cell assays including reporter assays, T-cell proliferation, mixed-lymphocyte reactions, and tumor-infiltrating lymphocyte assays.
- In vivo assessment in blood samples from patients with advanced solid tumors treated in a first-in-human clinical trial.
- Live-cell imaging was also employed for characterization.
Main Results:
- DuoBody-CD40×4-1BB demonstrated conditional agonist activity for CD40 and 4-1BB, dependent on target crosslinking.
- The antibody strengthened the DC/T-cell immunological synapse, induced DC maturation, and enhanced T-cell proliferation and effector functions.
- Combination with PD-1 blocking antibodies potentiated T-cell activation, and the antibody showed immune modulation in patients with advanced solid tumors.
Conclusions:
- DuoBody-CD40×4-1BB enhances anti-tumor immunity by modulating DC and T-cell functions.
- The antibody exhibits biological activity in patients with advanced solid tumors.
- Targeting CD40 and 4-1BB with an Fc-inert bispecific antibody is a promising strategy for reactivating tumor-specific immunity.
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