气候变化领域集成服务门户(CCPortal): An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications

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DOI	10.1073/pnas.2101852118
	An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications
	Millul J.; Bassi G.; Mock J.; Elsayed A.; Pellegrino C.; Zana A.; Plaza S.D.; Nadal L.; Gloger A.; Schmidt E.; Biancofiore I.; Donckele E.J.; Samain F.; Neri D.; Cazzamalli S.
发表日期	2021
ISSN	00278424
卷号	118 期号:16
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	FAP; Small molecule therapeutics; Tumor targeting
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179826
作者单位	Philochem AG, R&D Department, Otelfingen, CH-8112, Switzerland; Swiss Federal Institute of Technology, Department of Chemistry and Applied Biosciences, Zurich, CH-8093, Switzerland; Philogen S.p.A., Siena, 53100, Italy
推荐引用方式 GB/T 7714	Millul J.,Bassi G.,Mock J.,et al. An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications[J],2021,118(16).
APA	Millul J..,Bassi G..,Mock J..,Elsayed A..,Pellegrino C..,...&Cazzamalli S..(2021).An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications.Proceedings of the National Academy of Sciences of the United States of America,118(16).
MLA	Millul J.,et al."An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications".Proceedings of the National Academy of Sciences of the United States of America 118.16(2021).