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

Martina Geiger, Kay-Gunnar Stubenrauch, Johannes Sam, Wolfgang F. Richter, Gregor Jordan, Jan Eckmann, Carina Hage, Valeria Nicolini, Anne Freimoser-Grundschober, Mirko Ritter, Matthias E. Lauer, Henning Stahlberg, Philippe Ringler, Jigar Patel, Eric Sullivan, Sandra Grau-Richards, Stefan Endres, Sebastian Kobold, Pablo Umaña, Peter Brünker and Christian Klein ()
Additional contact information
Martina Geiger: Roche Innovation Center Zurich
Kay-Gunnar Stubenrauch: Roche Innovation Center Munich
Johannes Sam: Roche Innovation Center Zurich
Wolfgang F. Richter: Roche Innovation Center Basel
Gregor Jordan: Roche Innovation Center Munich
Jan Eckmann: Roche Innovation Center Munich
Carina Hage: Roche Innovation Center Munich
Valeria Nicolini: Roche Innovation Center Zurich
Anne Freimoser-Grundschober: Roche Innovation Center Zurich
Mirko Ritter: CPS Research and Development
Matthias E. Lauer: Roche Innovation Center Basel
Henning Stahlberg: Biozentrum, University of Basel
Philippe Ringler: Biozentrum, University of Basel
Jigar Patel: Roche Sequencing, NimbleGen
Eric Sullivan: Roche Sequencing, NimbleGen
Sandra Grau-Richards: Roche Innovation Center Zurich
Stefan Endres: Klinikum der Universität München
Sebastian Kobold: Klinikum der Universität München
Pablo Umaña: Roche Innovation Center Zurich
Peter Brünker: Roche Innovation Center Zurich
Christian Klein: Roche Innovation Center Zurich

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16838-w

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