TY - JOUR
T1 - ATTACK, a novel bispecific T cell-recruiting antibody with trivalent EGFR binding and monovalent CD3 binding for cancer immunotherapy
AU - Harwood, Seandean Lykke
AU - Alvarez-Cienfuegos, Ana
AU - Nuñez-Prado, Natalia
AU - Compte, Marta
AU - Hernández-Pérez, Sara
AU - Merino, Nekane
AU - Bonet, Jaume
AU - Navarro, Rocio
AU - Van Bergen en Henegouwen, Paul M.P.
AU - Lykkemark, Simon
AU - Mikkelsen, Kasper
AU - Mølgaard, Kasper
AU - Jabs, Frederic
AU - Sanz, Laura
AU - Blanco, Francisco J.
AU - Roda-Navarro, Pedro
AU - Alvarez-Vallina, Luis
N1 - Funding Information:
J.B. was supported from the ‘EPFL Fellows’ fellowship program co-funded by Marie Skłodowska-Curie, Horizon 2020 (665667). L.S. was supported by grants from the Fondo de Investigación Sanitaria/Instituto de Salud Carlos III (PI13/00090), co-funded by FEDER funds, and the Comunidad de Madrid (S2010/BMD-2312). F.J.B. was supported by the Spanish Ministry of Economy and Competitiveness (CTQ2014-56966-R). PR-N was funded by the Spanish Ministry of Economy and Competitiveness (SAF2016-75656-P), co-funded by FEDER funds. L.A-V. was supported by grants from the Danish Council for Independent Research, Medical Sciences (DFF-6110-00533), and the Novo Nordisk Foundation (NNF14OC0011019).
Publisher Copyright:
© 2018 The Author(s). Published with license by Taylor & Francis Group, LLC. © 2018, Seandean Lykke Harwood, Ana Alvarez-Cienfuegos, Natalia Nuñez-Prado, Marta Compte, Sara Hernández-Pérez, Nekane Merino, Jaume Bonet, Rocio Navarro, Paul M. P. van Bergen en Henegouwen, Simon Lykkemark, Kasper Mikkelsen, Kasper Mølgaard, Frederic Jabs, Laura Sanz, Francisco J. Blanco, Pedro Roda-Navarro, and Luis Alvarez-Vallina.
PY - 2018/1/2
Y1 - 2018/1/2
N2 - The redirection of T cell activity using bispecific antibodies is one of the most promising cancer immunotherapy approaches currently in development, but it is limited by cytokine storm-related toxicities, as well as the pharmacokinetics and tumor-penetrating capabilities of current bispecific antibody formats. Here, we have engineered the ATTACK (Asymmetric Tandem Trimerbody for T cell Activation and Cancer Killing), a novel T cell-recruiting bispecific antibody which combines three EGFR-binding single-domain antibodies (VHH; clone EgA1) with a single CD3-binding single-chain variable fragment (scFv; clone OKT3) in an intermediate molecular weight package. The two specificities are oriented in opposite directions in order to simultaneously engage cancer cells and T cell effectors, and thereby promote immunological synapse formation. EgA1 ATTACK was expressed as a homogenous, non-aggregating, soluble protein by mammalian cells and demonstrated an enhanced binding to EGFR, but not CD3, when compared to the previously characterized tandem bispecific antibody which has one EgA1 VHH and one OKT3 scFv per molecule. EgA1 ATTACK induced synapse formation and early signaling pathways downstream of TCR engagement at lower concentrations than the tandem VHH-scFv bispecific antibody. Furthermore, it demonstrated extremely potent, dose-dependent cytotoxicity when retargeting human T cells towards EGFR-expressing cells, with an efficacy over 15-fold higher than that of the tandem VHH-scFv bispecific antibody. These results suggest that the ATTACK is an ideal format for the development of the next-generation of T cell-redirecting bispecific antibodies.
AB - The redirection of T cell activity using bispecific antibodies is one of the most promising cancer immunotherapy approaches currently in development, but it is limited by cytokine storm-related toxicities, as well as the pharmacokinetics and tumor-penetrating capabilities of current bispecific antibody formats. Here, we have engineered the ATTACK (Asymmetric Tandem Trimerbody for T cell Activation and Cancer Killing), a novel T cell-recruiting bispecific antibody which combines three EGFR-binding single-domain antibodies (VHH; clone EgA1) with a single CD3-binding single-chain variable fragment (scFv; clone OKT3) in an intermediate molecular weight package. The two specificities are oriented in opposite directions in order to simultaneously engage cancer cells and T cell effectors, and thereby promote immunological synapse formation. EgA1 ATTACK was expressed as a homogenous, non-aggregating, soluble protein by mammalian cells and demonstrated an enhanced binding to EGFR, but not CD3, when compared to the previously characterized tandem bispecific antibody which has one EgA1 VHH and one OKT3 scFv per molecule. EgA1 ATTACK induced synapse formation and early signaling pathways downstream of TCR engagement at lower concentrations than the tandem VHH-scFv bispecific antibody. Furthermore, it demonstrated extremely potent, dose-dependent cytotoxicity when retargeting human T cells towards EGFR-expressing cells, with an efficacy over 15-fold higher than that of the tandem VHH-scFv bispecific antibody. These results suggest that the ATTACK is an ideal format for the development of the next-generation of T cell-redirecting bispecific antibodies.
KW - T cell redirection
KW - bispecific antibody
KW - cancer immunotherapy
KW - epithelial growth factor receptor
KW - trimerbody
UR - http://www.scopus.com/inward/record.url?scp=85030174497&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85030174497&partnerID=8YFLogxK
U2 - 10.1080/2162402X.2017.1377874
DO - 10.1080/2162402X.2017.1377874
M3 - Article
C2 - 29296540
AN - SCOPUS:85030174497
SN - 2162-4011
VL - 7
JO - OncoImmunology
JF - OncoImmunology
IS - 1
M1 - e1377874
ER -