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

  • Nat Commun. 2018 Nov 15;9(1):4809. doi: 10.1038/s41467-018-07195-w.
Marta Compte  1 ,  Seandean Lykke Harwood  2 ,  Ines G Muñoz  3 ,  Rocio Navarro  4 ,  Manuela Zonca  1 ,  Gema Perez-Chacon  5  6 ,  Ainhoa Erce-Llamazares  1 ,  Nekane Merino  7 ,  Antonio Tapia-Galisteo  4 ,  Angel M Cuesta  4 ,  Kasper Mikkelsen  2 ,  Eduardo Caleiras  8 ,  Natalia Nuñez-Prado  4 ,  M Angela Aznar  9 ,  Simon Lykkemark  2 ,  Jorge Martínez-Torrecuadrada  3 ,  Ignacio Melero  9  10  11  12 ,  Francisco J Blanco  7  13 ,  Jorge Bernardino de la Serna  14  15 ,  Juan M Zapata  5  6 ,  Laura Sanz  4 ,  Luis Alvarez-Vallina  16  17  18
Affiliations
  • 1. Department of Antibody Engineering, Leadartis SL, 28008, Madrid, Spain.
  • 2. Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, 8000C, Aarhus, Denmark.
  • 3. Crystallography and Protein Engineering Unit, Spanish National Cancer Research Centre (CNIO), 28029, Madrid, Spain.
  • 4. Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, 28222 Majadahonda, Madrid, Spain.
  • 5. Instituto de Investigaciones Biomédicas Alberto Sols (IIBm), CSIC-UAM, 28029, Madrid, Spain.
  • 6. Instituto de Investigación Sanitaria La Paz (IdiPaz), 28029, Madrid, Spain.
  • 7. Structural Biology Unit, CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160, Derio, Spain.
  • 8. Histopathology Unit, Spanish National Cancer Research Centre (CNIO), 28029, Madrid, Spain.
  • 9. Department of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
  • 10. Department of Immunology, University Clinic, University of Navarra, 31008 Pamplona, Spain.
  • 11. Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain.
  • 12. CIBERONC-Centro virtual de Investigación Biomédica en red de Oncología, 28029 Madrid, Spain.
  • 13. IKERBASQUE, Basque Foundation for Science, 48013, Bilbao, Spain.
  • 14. Central Laser Facility, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Research Complex at Harwell, OX11 0QX Harwell-Oxford, UK.
  • 15. Department of Physics, King's College London, WC2R 2LS London, UK.
  • 16. Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, 8000C, Aarhus, Denmark. [email protected].
  • 17. Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041, Madrid, Spain. [email protected].
  • 18. Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (i+12), 28041, Madrid, Spain. [email protected].
PMID: 30442944 DOI: 10.1038/s41467-018-07195-w
Abstract

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.

Products