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Nat Commun. 2018 Nov 15;9(1):4809. doi: 10.1038/s41467-018-07195-w.

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

Author information

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.

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.

PMID:
30442944
PMCID:
PMC6237851
DOI:
10.1038/s41467-018-07195-w
[Indexed for MEDLINE]
Free PMC Article

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