PuSH - Publikationsserver des Helmholtz Zentrums München: Protease-activation using anti-idiotypic masks enables tumor specificity of a folate receptor 1-T cell bispecific antibody.

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Geiger, M.* ; Stubenrauch, K.G.* ; Sam, J.* ; Richter, W.F.* ; Jordan, G.* ; Eckmann, J.* ; Hage, C.* ; Nicolini, V.* ; Freimoser-Grundschober, A.* ; Ritter, M.* ; Lauer, M.E.* ; Stahlberg, H.* ; Ringler, P.* ; Patel, J.* ; Sullivan, E.* ; Grau-Richards, S.* ; Endres, S. ; Kobold, S. ; Umaña, P.* ; Brünker, P.* ; Klein, C.*

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

Nat. Commun. 11:3196 (2020)

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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.

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