Protease-activation using anti-idiotypic masks enables tumor specificity of a folate receptor 1-T cell bispecific antibody

Geiger, Martina; Stubenrauch, Kay-Gunnar; Sam, Johannes; Richter, Wolfgang F.; Jordan, Gregor; Eckmann, Jan; Hage, Carina; Nicolini, Valeria; Freimoser-Grundschober, Anne; Ritter, Mirko; Lauer, Matthias E.; Stahlberg, Henning; Ringler, Philippe; Patel, Jigar; Sullivan, Eric; Grau-Richards, Sandra; Endres, Stefan; Kobold, Sebastian; Umana, Pablo; Bruenker, Peter und Klein, Christian (2020): Protease-activation using anti-idiotypic masks enables tumor specificity of a folate receptor 1-T cell bispecific antibody. In: Nature Communications, Bd. 11, Nr. 1, 3196

Abstract

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2041-1723
• Sprache: Englisch