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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)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords Humanized Monoclonal-antibody; Transmembrane Serine-protease; Epithelial Ovarian-cancer; Recombinant Immunotoxins; Prognostic Markers; Disulfide Bonds; Fv Fragments; T-cells; Expression; Matriptase
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 11, Issue: 1, Pages: , Article Number: 3196 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Unit for Clinical Pharmacology (KKG-EKLiP)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Immune Response and Infection
PSP Element(s) G-522100-001
DOI 10.1038/s41467-020-16838-w
WOS ID WOS:000548926500012
Scopus ID 85086823931
PubMed ID 32581215
Erfassungsdatum 2020-07-09
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