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

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  • Seandean Lykke Harwood
  • Ana Alvarez-Cienfuegos, Department of Antibody Engineering, Leadartis S.L., Spanien
  • Natalia Nuñez del Prado Alanes
  • ,
  • Marta Compte, Department of Antibody Engineering, Leadartis S.L., Spanien
  • Sara Hernández-Pérez, Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid 28040, Spain., Spanien
  • Nekane Merino, Structural Biology Unit; CIC bioGUNE, Parque Tecnológico de Bizkaia; Derio, Spain., Danmark
  • Jaume Bonet, École Polytechnique Fédérale de Lausanne, Danmark
  • Rocio Navarro, Molecular Immunology Unit. Hospital Universitario Puerta de Hierro, Spanien
  • Paul M.P. van Bergen en Henegouwen, Utrecht University, Utrecht, Holland
  • Simon Lykkemark
  • ,
  • Kasper Mikkelsen
  • ,
  • Kasper Mølgaard
  • ,
  • Frederic Jabs
  • ,
  • Laura Sanz, Hospital Universitario Clinica Puerta de Hierro, Spanien
  • Francisco J Blanco, Hospital Universitario Puerta de Hierro, Madrid, Spain., Danmark
  • Pedro Roda-Navarro, Universidad Complutense de Madrid, Spanien
  • Luis Álvarez-Vallina
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.
Antal sider14
StatusUdgivet - 2018

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