Suchergebnisse

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 FcγR interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8N/CEGa1, 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. The1D8N/CEGa1 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 1D8N/CEGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate FcγR 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. ; This study was supported by grants from the European Union [IACT Project (602262), iNEXT Project (1676) and a Marie Curie Career Integration Grant (PCIG13-GA-2013-618914)], the Ministerio de Economía y Competitividad (CTQ2017-83810-R, RTC-2016-5118-1, SAF2017-83267-C2-1-R, SAF2017-89437-P, and PTQ-16-08340), the Fondo de Investigación Sanitaria/Instituto de Salud Carlos III (PI16/00357 and PI16/00895), the UK Research and Innovation (18130023), and the Danish Council for Independent Research (DFF-6110-0053). The CIC bioGUNE is a Severo Ochoa Center of Excellence (Ministerio de Economia y Competitividad award SEV-2016-0644). This study was also funded by FEDER. ; Peer reviewed

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 FcγR interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8N/CEGa1, 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. The1D8N/CEGa1 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 1D8N/CEGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate FcγR 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. ; We thank M. Jure-Kunkel, M. Rescigno and A. Villalobo for reagents, M.G. Gonzalez Bueno and B. Acosta (IIBm) for technical support, and the staff of beamline B21at Diamond Light Source (Didcot, UK) for their excellent technical assistance. This study was supported by grants from the European Union [IACT Project (602262), iNEXT Project (1676) and a Marie Curie Career Integration Grant (PCIG13-GA-2013-618914)], the Ministerio de Economía y Competitividad (CTQ2017-83810-R, RTC-2016-5118-1, SAF2017-83267-C2-1-R, SAF2017-89437-P, and PTQ-16-08340), the Fondo de Investigación Sanitaria/Instituto de Salud Carlos III (PI16/00357 and PI16/00895), the UK Research and Innovation (18130023), and the Danish Council for Independent Research (DFF-6110-0053). The CIC bioGUNE is a Severo Ochoa Center of Excellence (Ministerio de Economia y Competitividad award SEV-2016-0644). This study was also funded by FEDER. ; Sí