| Autor: |
Luis Alvarez-Vallina, Laura Sanz, Luis Paz-Ares, José L. Rodriguez-Peralto, Ignacio Melero, Ines G. Muñoz, Miguel A. Morcillo, Francisco J. Blanco, Angel Ramírez-Fernández, Manuela Zonca, Carmen Domínguez-Alonso, Oana Hangiu, Daniel Nehme-Álvarez, Nekane Merino, Marta Oteo, Belén Blanco, Maria C. Ochoa, Ana B. Enguita, Eva M. Garrido-Martin, Irene Ferrer, Eduardo Romero, Antonio Tapia-Galisteo, Ainhoa Erce-Llamazares, Seandean L. Harwood, Marta Compte |
| Rok vydání: |
2023 |
| DOI: |
10.1158/1078-0432.c.6530226 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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