Pérez-Chacon, G. (Gema)

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    A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity
    (2018) Pérez-Chacon, G. (Gema); Álvarez-Vallina, L. (Luis); Harwood, S.L. (Seandean Lykke); Muñoz, I.G. (Inés G.); Compte, M. (Marta); Merino, N. (Nekane); Zapata, J.M. (Juan M.); Núñez-Prado, N. (Natalia); Aznar, M.A. (María Ángela); Blanco, F.J. (Francisco J.); Erce-Llamazares, A. (Ainhoa); Cuesta, A.M. (Ángel M.); Sanz, L. (Laura); Mikkelsen, K. (Kasper); Martínez-Torrecuadrada, J. (Jorge); Melero, I. (Ignacio); Caleiras, E. (Eduardo); Tapia-Galisteo, A. (Alberto); Zonca, M. (Manuela); Serna, J.B. (Jorge Bernardino) de la; Lykkemark, S. (Simon); Navarro, R. (Rocío)
    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 Fc gamma R interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8(N)/(C)EGa1, 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. The1D8(N)/(C)EGa1 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 1D8(N)/(C)EGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate Fc gamma R 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.