ATTACK, a novel bispecific T cell-recruiting antibody with trivalent EGFR binding and monovalent CD3 binding for cancer immunotherapy

Seandean Lykke Harwood; Ana Alvarez-Cienfuegos; Natalia Nuñez del Prado Alanes; 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; Luis Álvarez-Vallina

doi:10.1080/2162402X.2017.1377874

ATTACK, a novel bispecific T cell-recruiting antibody with trivalent EGFR binding and monovalent CD3 binding for cancer immunotherapy

Seandean Lykke Harwood, Ana Alvarez-Cienfuegos, Natalia Nuñez del Prado Alanes, 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, Luis Álvarez-Vallina

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Abstract

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.

Original language	English
Article number	e1377874
Journal	OncoImmunology
Volume	7
Issue	1
Number of pages	14
ISSN	2162-4011
DOIs	https://doi.org/10.1080/2162402X.2017.1377874
Publication status	Published - 2018

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Harwood, S. L., Alvarez-Cienfuegos, A., Alanes, N. N. D. P., Compte, M., Hernández-Pérez, S., Merino, N., Bonet, J., Navarro, R., M.P. van Bergen en Henegouwen, P., Lykkemark, S., Mikkelsen, K., Mølgaard , K., Jabs, F., Sanz, L., Blanco, F. J., Roda-Navarro, P., & Álvarez-Vallina, L. (2018). ATTACK, a novel bispecific T cell-recruiting antibody with trivalent EGFR binding and monovalent CD3 binding for cancer immunotherapy. OncoImmunology, 7(1), Article e1377874. https://doi.org/10.1080/2162402X.2017.1377874

@article{c6fd2cb33de7420a91d2bf4d184ea165,

title = "ATTACK, a novel bispecific T cell-recruiting antibody with trivalent EGFR binding and monovalent CD3 binding for cancer immunotherapy",

abstract = "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.",

author = "Harwood, {Seandean Lykke} and Ana Alvarez-Cienfuegos and Alanes, {Natalia Nu{\~n}ez del Prado} and Marta Compte and Sara Hern{\'a}ndez-P{\'e}rez and Nekane Merino and Jaume Bonet and Rocio Navarro and {M.P. van Bergen en Henegouwen}, Paul and Simon Lykkemark and Kasper Mikkelsen and Kasper M{\o}lgaard and Frederic Jabs and Laura Sanz and Blanco, {Francisco J} and Pedro Roda-Navarro and Luis {\'A}lvarez-Vallina",

year = "2018",

doi = "10.1080/2162402X.2017.1377874",

language = "English",

volume = "7",

journal = "OncoImmunology",

issn = "2162-4011",

publisher = "Taylor & Francis Inc.",

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Harwood, SL, Alvarez-Cienfuegos, A, Alanes, NNDP, Compte, M, Hernández-Pérez, S, Merino, N, Bonet, J, Navarro, R, M.P. van Bergen en Henegouwen, P, Lykkemark, S, Mikkelsen, K, Mølgaard , K, Jabs, F, Sanz, L, Blanco, FJ, Roda-Navarro, P & Álvarez-Vallina, L 2018, 'ATTACK, a novel bispecific T cell-recruiting antibody with trivalent EGFR binding and monovalent CD3 binding for cancer immunotherapy', OncoImmunology, vol. 7, no. 1, e1377874. https://doi.org/10.1080/2162402X.2017.1377874

ATTACK, a novel bispecific T cell-recruiting antibody with trivalent EGFR binding and monovalent CD3 binding for cancer immunotherapy. / Harwood, Seandean Lykke; Alvarez-Cienfuegos, Ana; Alanes, Natalia Nuñez del Prado et al.
In: OncoImmunology, Vol. 7, No. 1, e1377874, 2018.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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 - Alanes, Natalia Nuñez del Prado

AU - Compte, Marta

AU - Hernández-Pérez, Sara

AU - Merino, Nekane

AU - Bonet, Jaume

AU - Navarro, Rocio

AU - M.P. van Bergen en Henegouwen, Paul

AU - Lykkemark, Simon

AU - Mikkelsen, Kasper

AU - Mølgaard , Kasper

AU - Jabs, Frederic

AU - Sanz, Laura

AU - Blanco, Francisco J

AU - Roda-Navarro, Pedro

AU - Álvarez-Vallina, Luis

PY - 2018

Y1 - 2018

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.

U2 - 10.1080/2162402X.2017.1377874

DO - 10.1080/2162402X.2017.1377874

M3 - Journal article

C2 - 29296540

SN - 2162-4011

VL - 7

JO - OncoImmunology

JF - OncoImmunology

IS - 1

M1 - e1377874

ER -

ATTACK, a novel bispecific T cell-recruiting antibody with trivalent EGFR binding and monovalent CD3 binding for cancer immunotherapy

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