@article{Compte:2018:10.1038/s41467-018-07195-w,
author = {Compte, M and Lykke, Harwood S and Munoz, IG and Navarro, R and Zonca, M and Perez-Chacon, G and Erce-Llamazares, A and Merino, N and Tapia-Galisteo, A and Cuesta, AM and Mikkelsen, K and Caleiras, E and Nunez-Prado, N and Aznar, MA and Lykkemark, S and Martinez-Torrecuadrada, J and Melero, I and Blanco, FJ and Bernardino, de la Serna J and Zapata, JM and Sanz, L and Alvarez-Vallina, L},
doi = {10.1038/s41467-018-07195-w},
journal = {Nature Communications},
title = {A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity},
url = {http://dx.doi.org/10.1038/s41467-018-07195-w},
volume = {9},
year = {2018}
}

Download

TY  - JOUR
AB  - 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.
AU  - Compte,M
AU  - Lykke,Harwood S
AU  - Munoz,IG
AU  - Navarro,R
AU  - Zonca,M
AU  - Perez-Chacon,G
AU  - Erce-Llamazares,A
AU  - Merino,N
AU  - Tapia-Galisteo,A
AU  - Cuesta,AM
AU  - Mikkelsen,K
AU  - Caleiras,E
AU  - Nunez-Prado,N
AU  - Aznar,MA
AU  - Lykkemark,S
AU  - Martinez-Torrecuadrada,J
AU  - Melero,I
AU  - Blanco,FJ
AU  - Bernardino,de la Serna J
AU  - Zapata,JM
AU  - Sanz,L
AU  - Alvarez-Vallina,L
DO  - 10.1038/s41467-018-07195-w
PY  - 2018///
SN  - 2041-1723
TI  - A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity
T2  - Nature Communications
UR  - http://dx.doi.org/10.1038/s41467-018-07195-w
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000450161100009&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/69261
VL  - 9
ER  - 

Download