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

DOI: 10.1038/s41467-018-07195-w DOI Help

Authors: Marta Compte (Leadartis SL) , Seandean Lykke Harwood (Aarhus University) , Ines G. Munoz (Spanish National Cancer Research Centre (CNIO)) , Rocio Navarro (Hospital Universitario Puerta de Hierro Majadahonda) , Manuela Zonca (Leadartis SL) , Gema Perez-Chacon (Instituto de Investigaciones Biomédicas Alberto Sols (IIBm), CSIC-UAM) , Ainhoa Erce-Llamazares (Leadartis SL) , Nekane Merino (CIC bioGUNE) , Antonio Tapia-Galisteo (Hospital Universitario Puerta de Hierro Majadahonda) , Angel M. Cuesta (Hospital Universitario Puerta de Hierro Majadahonda) , Kasper Mikkelsen (Hospital Universitario Puerta de Hierro Majadahonda) , Eduardo Caleiras (Spanish National Cancer Research Centre (CNIO)) , Natalia Nuñez-Prado (Hospital Universitario Puerta de Hierro Majadahonda) , M. Angela Aznar (University of Navarra) , Simon Lykkemark (Aarhus University) , Jorge Martínez-Torrecuadrada (Spanish National Cancer Research Centre (CNIO)) , Ignacio Melero (University of Navarra; Instituto de Investigación Sanitaria de Navarra (IdISNA); CIBERONC-Centro virtual de Investigación Biomédica en red de Oncología) , Francisco J. Blanco (CIC bioGUNE; IKERBASQUE, Basque Foundation for Science) , Jorge Bernardino De La Serna (Central Laser Facility, Research Complex at Harwell; King’s College London) , Juan M. Zapata (Instituto de Investigaciones Biomédicas Alberto Sols (IIBm); Instituto de Investigación Sanitaria La Paz (IdiPaz)) , Laura Sanz (Hospital Universitario Puerta de Hierro Majadahonda) , Luis Alvarez-Vallina (Aarhus University; Hospital Universitario 12 de Octubre; Instituto de Investigación Sanitaria 12 de Octubre (i+12))
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Nature Communications , VOL 9

State: Published (Approved)
Published: November 2018

Open Access Open Access

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.

Journal Keywords: Cancer; Cancer therapy; Molecular engineering; Tumour immunology

Diamond Keywords: Immunotherapy

Subject Areas: Biology and Bio-materials, Medicine

Instruments: B21-High Throughput SAXS

Added On: 22/11/2018 11:10


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)