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

Title: A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity
Authors: Compte, M
Lykke Harwood, S
Munoz, IG
Navarro, R
Zonca, M
Perez-Chacon, G
Erce-Llamazares, A
Merino, N
Tapia-Galisteo, A
Cuesta, AM
Mikkelsen, K
Caleiras, E
Nunez-Prado, N
Aznar, MA
Lykkemark, S
Martinez-Torrecuadrada, J
Melero, I
Blanco, FJ
Bernardino de la Serna, J
Zapata, JM
Sanz, L
Alvarez-Vallina, L
Item Type: Journal Article
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.
Issue Date: 15-Nov-2018
Date of Acceptance: 17-Oct-2018
URI: http://hdl.handle.net/10044/1/69261
DOI: https://doi.org/10.1038/s41467-018-07195-w
ISSN: 2041-1723
Publisher: Nature Research (part of Springer Nature)
Journal / Book Title: Nature Communications
Volume: 9
Issue: 1
Copyright Statement: © 2018 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
Adaptive Immunity
CD8-Positive T-Lymphocytes
Cell Line, Tumor
Cytotoxicity, Immunologic
Epitope Mapping
Epitopes, B-Lymphocyte
ErbB Receptors
Immunoglobulin G
Lymphocytes, Tumor-Infiltrating
Mice, Inbred BALB C
Mice, Nude
Single-Chain Antibodies
Skin Neoplasms
Tumor Necrosis Factor Receptor Superfamily, Member 9
Xenograft Model Antitumor Assays
MD Multidisciplinary
Publication Status: Published
Article Number: 4809
Online Publication Date: 2018-11-15
Appears in Collections:National Heart and Lung Institute
Airway Disease
Faculty of Medicine

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