Protease-activation using anti-idiotypic masks enables tumor specificity of a folate receptor 1-T cell bispecific antibody.
Détails
ID Serval
serval:BIB_26320D7A35D5
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Protease-activation using anti-idiotypic masks enables tumor specificity of a folate receptor 1-T cell bispecific antibody.
Périodique
Nature communications
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Statut éditorial
Publié
Date de publication
24/06/2020
Peer-reviewed
Oui
Volume
11
Numéro
1
Pages
3196
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Publication Status: epublish
Résumé
T-cell bispecific antibodies (TCBs) crosslink tumor and T-cells to induce tumor cell killing. While TCBs are very potent, on-target off-tumor toxicity remains a challenge when selecting targets. Here, we describe a protease-activated anti-folate receptor 1 TCB (Prot-FOLR1-TCB) equipped with an anti-idiotypic anti-CD3 mask connected to the anti-CD3 Fab through a tumor protease-cleavable linker. The potency of this Prot- FOLR1-TCB is recovered following protease-cleavage of the linker releasing the anti-idiotypic anti-CD3 scFv. In vivo, the Prot-FOLR1-TCB mediates antitumor efficacy comparable to the parental FOLR1-TCB whereas a noncleavable control Prot-FOLR1-TCB is inactive. In contrast, killing of bronchial epithelial and renal cortical cells with low FOLR1 expression is prevented compared to the parental FOLR1-TCB. The findings are confirmed for mesothelin as alternative tumor antigen. Thus, masking the anti-CD3 Fab fragment with an anti-idiotypic mask and cleavage of the mask by tumor-specific proteases can be applied to enhance specificity and safety of TCBs.
Mots-clé
Animals, Antibodies, Bispecific/chemistry, Antibodies, Bispecific/immunology, Antibodies, Bispecific/metabolism, Antibodies, Bispecific/therapeutic use, CD3 Complex/immunology, Cell Line, Tumor, Folate Receptor 1/immunology, GPI-Linked Proteins/immunology, Humans, Immunotherapy, Lymphocyte Activation/drug effects, Mesothelin, Mice, Molecular Targeted Therapy, Peptide Hydrolases/metabolism, T-Lymphocytes/immunology, Xenograft Model Antitumor Assays
Pubmed
Web of science
Open Access
Oui
Création de la notice
09/06/2023 15:02
Dernière modification de la notice
08/07/2023 5:50