2. Academic Validation
  3. A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity

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

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. lav@eng.au.dk.
  • 17 Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041, Madrid, Spain. lav@eng.au.dk.
  • 18 Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (i+12), 28041, Madrid, Spain. lav@eng.au.dk.
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.

Figures
Products