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An Fc-free EGFR-specific 4-1BB-agonistic trimerbody displays broad anti-tumor activity in humanized murine cancer models without toxicity

DOI: 10.1158/1078-0432.CCR-20-4625 DOI Help

Authors: Marta Compte (Leadartis SL) , Seandean L. Harwood (Aarhus University) , Ainhoa Erce-Llamazares (Leadartis SL) , Antonio Tapia-Galisteo (Biomedical Research Institute Hospital Puerta de Hierro) , Eduardo Romero (CIEMAT) , Irene Ferrer (Instituto de Investigación Hospital 12 de Octubre) , Eva M Garrido-Martin (H12O-CNIO) , Ana B. Enguita (Hospital Universitario 12 De Octubre) , Maria C Ochoa (University of Navarra) , Belen Blanco (Hospital Universitario 12 De Octubre) , Marta Oteo (Instituto de Investigación 12 de Octubre i+12) , Nekane Merino (CIC bioGUNE) , Daniel Nehme-Alvarez (Hospital Universitario 12 De Octubre) , Oana Hangiu (Hospital Universitario 12 De Octubre) , Carmen Domínguez-Alonso (Hospital Universitario 12 De Octubre) , Manuela Zonca (Leadartis SL) , Angel Ramírez-Fernández (Hospital Universitario 12 De Octubre) , Francisco J. Blanco (Centro de Investigaciones Biológicas) , Miguel Angel Morcillo (CIEMAT) , Ines G. Munoz (CNIO) , Ignacio Melero (University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA)) , José L. Rodríguez-Peralto (Hospital Universitario 12 de Octubre; Universidad Complutense) , Luis G. Paz-Ares (Instituto de Biomedicina de Sevilla - IBIS (University Hospital Virgen del Rocio, US, CSIC)) , Laura Sanz (Biomedical Research Institute Hospital Puerta de Hierro-Segovia de Arana) , Luis Álvarez-Vallina (Hospital Universitario 12 De Octubre)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Clinical Cancer Research

State: Published (Approved)
Published: March 2021
Diamond Proposal Number(s): 20450

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 anti-tumor response. Systemic administration of anti-4-1BB-agonistic IgGs, althougheffective 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, anti-tumor 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 anti-tumor 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 IFNg secretion in vitro and resulted in tumor regression in humanized mice bearing aggressive triple-negative breast cancer. Conclusions: These results demonstrate the non-toxic broad anti-tumor 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 cancer patients while avoiding Fc-mediated adverse reactions.

Journal Keywords: Immunotherapy

Subject Areas: Biology and Bio-materials, Medicine

Instruments: B21-High Throughput SAXS

Added On: 08/04/2021 08:44

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Drug Discovery Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)