PT  - JOURNAL ARTICLE
AU  - Muik, Alexander
AU  - Adams, Homer C
AU  - Gieseke, Friederike
AU  - Altintas, Isil
AU  - Schoedel, Kristina B
AU  - Blum, Jordan M
AU  - Sänger, Bianca
AU  - Burm, Saskia M
AU  - Stanganello, Eliana
AU  - Verzijl, Dennis
AU  - Spires, Vanessa M
AU  - Vascotto, Fulvia
AU  - Toker, Aras
AU  - Quinkhardt, Juliane
AU  - Fereshteh, Mark
AU  - Diken, Mustafa
AU  - Satijn, David P E
AU  - Kreiter, Sebastian
AU  - Ahmadi, Tahamtan
AU  - Breij, Esther C W
AU  - Türeci, Özlem
AU  - Sasser, Kate
AU  - Sahin, Ugur
AU  - Jure-Kunkel, Maria
TI  - DuoBody-CD40x4-1BB induces dendritic-cell maturation and enhances T-cell activation through conditional CD40 and 4-1BB agonist activity
AID  - 10.1136/jitc-2021-004322
DP  - 2022 Jun 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e004322
VI  - 10
IP  - 6
4099  - http://jitc.bmj.com/content/10/6/e004322.short
4100  - http://jitc.bmj.com/content/10/6/e004322.full
SO  - J Immunother Cancer2022 Jun 01; 10
AB  - 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.Data are available on reasonable request. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.