Trimerbodies, with their unique structural and functional properties, are the basis of a new generation of therapeutic antibodies, which due to their small size and plasticity are ideal for the generation of novel biological protein drugs with multiple competitive advantages over conventional full-length monoclonal antibodies. Since their emergence, trimerbodies have been used in preclinical cancer diagnosis and therapy. Trimerbodies are highly adaptable molecules, as they allow target-specific modulation of T cell-mediated anti-tumor immunity to enhance preexisting responses or to generate de novo immune responses. In fact, a tumor-specific humanized 4-1BB-agonistic trimerbody has shown a rather impressive safety and efficacy profile in preclinical studies making it a realistic option for clinical development. Moreover, thanks to the avidity effect they are endowed with considerable therapeutic potential as carriers to deliver cytotoxic payloads to tumors. In addition, molecular imaging studies could benefit from some intermediate-sized trivalent trimerbodies as promising candidates for targeted therapy and tumor imaging.
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http://dx.doi.org/10.1016/bs.ircmb.2022.03.008 | DOI Listing |
Toxicol Appl Pharmacol
June 2024
Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain; Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain; H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain. Electronic address:
LEAD-452 is a humanized bispecific EGFR-targeted 4-1BB-agonistic trimerbody with a unique trimeric configuration compared to other 4-1BB-specific antibodies that are currently in development. Indeed, enhanced tumor-specific costimulation and very remarkable safety and efficacy profiles have been observed in mouse models. Here, we conducted for the first time a preclinical pharmacokinetic and toxicity study in non-human primates (NHP) (Macaca fascicularis).
View Article and Find Full Text PDFInt Rev Cell Mol Biol
July 2022
Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain; Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain. Electronic address:
Trimerbodies, with their unique structural and functional properties, are the basis of a new generation of therapeutic antibodies, which due to their small size and plasticity are ideal for the generation of novel biological protein drugs with multiple competitive advantages over conventional full-length monoclonal antibodies. Since their emergence, trimerbodies have been used in preclinical cancer diagnosis and therapy. Trimerbodies are highly adaptable molecules, as they allow target-specific modulation of T cell-mediated anti-tumor immunity to enhance preexisting responses or to generate de novo immune responses.
View Article and Find Full Text PDFClin Cancer Res
June 2021
Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus, Denmark.
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.
Mol Pharm
March 2019
Radiochemistry and Nuclear Imaging Group , CIC biomaGUNE , 20014 San Sebastián , Guipúzcoa , Spain.
Monoclonal antibodies (mAbs) are currently used as therapeutic agents in different types of cancer. However, mAbs and antibody fragments developed so far show suboptimal properties in terms of circulation time and tumor penetration/retention. Here, we report the radiolabeling, pharmacokinetic evaluation, and determination of tumor targeting capacity of the previously validated anti-CEA MFE23-scFv-based N-terminal trimerbody (MFE23-trimerbody), and the results are compared to those obtained for the monomeric MFE23-scFv.
View Article and Find Full Text PDFSci Rep
June 2016
Department of Engineering, Aarhus University, Gustav Wieds Vej 10, 8000 C Aarhus, Denmark.
Here, we describe a new strategy that allows the rapid and efficient engineering of mono and multispecific trivalent antibodies. By fusing single-domain antibodies from camelid heavy-chain-only immunoglobulins (VHHs) to the N-terminus of a human collagen XVIII trimerization domain (TIE(XVIII)) we produced monospecific trimerbodies that were efficiently secreted as soluble functional proteins by mammalian cells. The purified VHH-TIE(XVIII) trimerbodies were trimeric in solution and exhibited excellent antigen binding capacity.
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