An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications

We describe the development of OncoFAP, an ultra-high-affinity ligand of fibroblast activation protein (FAP) for targeting applications with pan-tumoral potential. OncoFAP binds to human FAP with affinity in the subnanomolar concentration range and cross-reacts with the murine isoform of the protein...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2021-04, Vol.118 (16), p.1-10
Hauptverfasser: Millul, Jacopo, Bassi, Gabriele, Mock, Jacqueline, Elsayed, Abdullah, Pellegrino, Christian, Zana, Aureliano, Plaza, Sheila Dakhel, Nadal, Lisa, Gloger, Andreas, Schmidt, Eleonore, Biancofiore, Ilaria, Donckele, Etienne J., Samain, Florent, Neri, Dario, Cazzamalli, Samuele
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container_title Proceedings of the National Academy of Sciences - PNAS
container_volume 118
creator Millul, Jacopo
Bassi, Gabriele
Mock, Jacqueline
Elsayed, Abdullah
Pellegrino, Christian
Zana, Aureliano
Plaza, Sheila Dakhel
Nadal, Lisa
Gloger, Andreas
Schmidt, Eleonore
Biancofiore, Ilaria
Donckele, Etienne J.
Samain, Florent
Neri, Dario
Cazzamalli, Samuele
description We describe the development of OncoFAP, an ultra-high-affinity ligand of fibroblast activation protein (FAP) for targeting applications with pan-tumoral potential. OncoFAP binds to human FAP with affinity in the subnanomolar concentration range and cross-reacts with the murine isoform of the protein. We generated various fluorescent and radiolabeled derivatives of OncoFAP in order to study biodistribution properties and tumor-targeting performance in preclinical models. Fluorescent derivatives selectively localized in FAP-positive tumors implanted in nude mice with a rapid and homogeneous penetration within the neoplastic tissue. Quantitative in vivo biodistribution studies with a lutetium-177–labeled derivative of OncoFAP revealed a preferential localization in tumors at doses of up to 1,000 nmol/kg. More than 30% of the injected dose had already accumulated in 1 g of tumor 10 min after intravenous injection and persisted for at least 3 h with excellent tumor-to-organ ratios. OncoFAP also served as a modular component for the generation of nonradioactive therapeutic products. A fluorescein conjugate mediated a potent and FAP-dependent tumor cell killing activity in combination with chimeric antigen receptor (CAR) T cells specific to fluorescein. Similarly, a conjugate of OncoFAP with the monomethyl auristatin E-based Vedotin payload was well tolerated and cured tumor-bearing mice in combination with a clinical-stage antibody-interleukin-2 fusion. Collectively, these data support the development of OncoFAP-based products for tumor-targeting applications in patients with cancer.
doi_str_mv 10.1073/pnas.2101852118
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OncoFAP binds to human FAP with affinity in the subnanomolar concentration range and cross-reacts with the murine isoform of the protein. We generated various fluorescent and radiolabeled derivatives of OncoFAP in order to study biodistribution properties and tumor-targeting performance in preclinical models. Fluorescent derivatives selectively localized in FAP-positive tumors implanted in nude mice with a rapid and homogeneous penetration within the neoplastic tissue. Quantitative in vivo biodistribution studies with a lutetium-177–labeled derivative of OncoFAP revealed a preferential localization in tumors at doses of up to 1,000 nmol/kg. More than 30% of the injected dose had already accumulated in 1 g of tumor 10 min after intravenous injection and persisted for at least 3 h with excellent tumor-to-organ ratios. OncoFAP also served as a modular component for the generation of nonradioactive therapeutic products. A fluorescein conjugate mediated a potent and FAP-dependent tumor cell killing activity in combination with chimeric antigen receptor (CAR) T cells specific to fluorescein. Similarly, a conjugate of OncoFAP with the monomethyl auristatin E-based Vedotin payload was well tolerated and cured tumor-bearing mice in combination with a clinical-stage antibody-interleukin-2 fusion. 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subjects Affinity
Antibodies
Antigens
Biodistribution
Biological Sciences
Chimeric antigen receptors
Conjugates
Fibroblast activation protein
Fibroblasts
Fluorescein
Fluorescence
In vivo methods and tests
Interleukin 2
Intravenous administration
Ligands
Localization
Lutetium
Lymphocytes
Lymphocytes T
Proteins
Surgical implants
Tumors
title An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications
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