Article open access publication

A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity

Nature Communications, Springer Nature, ISSN 2041-1723

Volume 9, 1, 2018

DOI:10.1038/s41467-018-07195-w, Dimensions: pub.1109841462, PMC: PMC6237851, PMID: 30442944,



  1. (1) Department of Antibody Engineering, Leadartis SL, 28008, Madrid, Spain
  2. (2) Aarhus University, grid.7048.b, AU
  3. (3) Spanish National Cancer Research Centre, grid.7719.8
  4. (4) Hospital Universitario Puerta de Hierro Majadahonda, grid.73221.35
  5. (5) Alberto Sols Biomedical Research Institute, grid.466793.9
  6. (6) Instituto de Investigación Sanitaria La Paz (IdiPaz), 28029, Madrid, Spain
  7. (7) Structural Biology Unit, CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160, Derio, Spain
  8. (8) University of Navarra, grid.5924.a
  9. (9) CIBERONC-Centro virtual de Investigación Biomédica en red de Oncología, 28029 Madrid, Spain
  10. (10) Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain
  11. (11) Ikerbasque, grid.424810.b
  12. (12) King's College London, grid.13097.3c
  13. (13) Rutherford Appleton Laboratory, grid.76978.37
  14. (14) Hospital Universitario 12 De Octubre, grid.144756.5
  15. (15) Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (i+12), 28041, Madrid, Spain


United Kingdom






The costimulation of immune cells using first-generation anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials. Further clinical development, however, is restricted by significant off-tumor toxicities associated with FcγR interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8N/CEGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single-domain antibodies positioned in an extended hexagonal conformation around the collagen XVIII homotrimerization domain. The1D8N/CEGa1 trimerbody demonstrated high-avidity binding to 4-1BB and EGFR and a potent in vitro costimulatory capacity in the presence of EGFR. The trimerbody rapidly accumulates in EGFR-positive tumors and exhibits anti-tumor activity similar to IgG-based 4-1BB-agonistic mAbs. Importantly, treatment with 1D8N/CEGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate FcγR interactions in the 4-1BB-agonist-associated immune abnormalities, and promote the use of the non-canonical antibody presented in this work for safe and effective costimulatory strategies in cancer immunotherapy.


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Times Cited: 31

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