2. Academic Validation
  3. DuoBody-CD40x4-1BB induces dendritic-cell maturation and enhances T-cell activation through conditional CD40 and 4-1BB agonist activity

DuoBody-CD40x4-1BB induces dendritic-cell maturation and enhances T-cell activation through conditional CD40 and 4-1BB agonist activity

  • J Immunother Cancer. 2022 Jun;10(6):e004322. doi: 10.1136/jitc-2021-004322.
Alexander Muik 1,  Homer C Adams 3rd 2,  Friederike Gieseke 1,  Isil Altintas 3,  Kristina B Schoedel 1,  Jordan M Blum 2,  Bianca Sänger 1,  Saskia M Burm 3,  Eliana Stanganello 4,  Dennis Verzijl 3,  Vanessa M Spires 2,  Fulvia Vascotto 4,  Aras Toker 1,  Juliane Quinkhardt 1,  Mark Fereshteh 2,  Mustafa Diken 1,  David P E Satijn 5,  Sebastian Kreiter 1,  Tahamtan Ahmadi 6,  Esther C W Breij 3,  Özlem Türeci 1,  Kate Sasser 2,  Ugur Sahin 1 4,  Maria Jure-Kunkel 7
Affiliations

Affiliations

  • 1 BioNTech SE, Mainz, Germany.
  • 2 Genmab US Inc, Plainsboro, New Jersey, USA.
  • 3 Translational Research and Precision Medicine, Genmab BV, Utrecht, The Netherlands.
  • 4 TRON-Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Mainz, Germany.
  • 5 Genmab BV, Utrecht, The Netherlands.
  • 6 Experimental Medicine, Genmab US Inc, Plainsboro, New Jersey, USA.
  • 7 Genmab US Inc, Plainsboro, New Jersey, USA mjk@genmab.com.
PMID: 35688554 DOI: 10.1136/jitc-2021-004322
Abstract

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.

Keywords

T-lymphocytes; dendritic cells; immunotherapy.

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