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An Fc-free EGFR-specific 4-1BB-agonistic trimerbody displays broad antitumor activity in humanized murine cancer models without toxicity
|Other Titles:||Running title: Non-toxic broad anti-tumor activity of an EGFR×4-1BB bispecific trimerbod|
|Authors:||Compte, Marta ; Harwood, Seandean Lykke; Erce-Llamazares, Ainhoa; Tapia-Galisteo, Antonio; Romero, Eduardo ; Ferrer, Irene; Garrido-Martin, Eva M. CSIC ORCID; Enguita, Ana Belén ; Ochoa, Maria Carmen ; Blanco, Belén; Oteo, Marta; Merino, Nekane ; Nehme-Álvarez, Daniel ; Hangiu, Oana; Domínguez-Alonso, Carmen ; Zonca, Manuela ; Ramírez-Fernández, Ángel ; Blanco, Francisco J. ORCID ; Morcillo, Miguel Ángel; Muñoz, Inés G.; Melero, Ignacio; Rodríguez-Peralto, J. L.; Paz-Ares, Luis CSIC; Sanz, Laura; Alvarez-Vallina, Luis|
|Publisher:||American Association for Cancer Research|
|Citation:||Clinical Cancer Research 27:3167-3177 (2021)|
|Abstract:||Purpose: The induction of 4-1BB signaling by agonistic antibodies can drive the activation and proliferation of effector T cells and thereby enhance a T-cell–mediated antitumor response. Systemic administration of anti-4-1BB–agonistic IgGs, although effective preclinically, has not advanced in clinical development due to their severe hepatotoxicity.|
Experimental Design: Here, we generated a humanized EGFR-specific 4-1BB-agonistic trimerbody, which replaces the IgG Fc region with a human collagen homotrimerization domain. It was characterized by structural analysis and in vitro functional studies. We also assessed pharmacokinetics, antitumor efficacy, and toxicity in vivo.
Results: In the presence of a T-cell receptor signal, the trimerbody provided potent T-cell costimulation that was strictly dependent on 4-1BB hyperclustering at the point of contact with a tumor antigen-displaying cell surface. It exhibits significant antitumor activity in vivo, without hepatotoxicity, in a wide range of human tumors including colorectal and breast cancer cell-derived xenografts, and non–small cell lung cancer patient-derived xenografts associated with increased tumor-infiltrating CD8+ T cells. The combination of the trimerbody with a PD-L1 blocker led to increased IFNγ secretion in vitro and resulted in tumor regression in humanized mice bearing aggressive triple-negative breast cancer.
Conclusions: These results demonstrate the nontoxic broad antitumor activity of humanized Fc-free tumor-specific 4-1BB-agonistic trimerbodies and their synergy with checkpoint blockers, which may provide a way to elicit responses in most patients with cancer while avoiding Fc-mediated adverse reactions.
|Description:||32 p.-4 fig.|
|Publisher version (URL):||https://doi.org/10.1158/1078-0432.CCR-20-4625|
|Appears in Collections:||(CIB) Artículos|
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