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

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

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Official URL: https://edoc.unibas.ch/77542/

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Structural Biology (Stahlberg)
UniBasel Contributors:Stahlberg, Henning
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Publishing Group
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:24 Nov 2021 16:31
Deposited On:24 Nov 2021 16:31

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