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
  • 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 [email protected].
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.
Products