Selective tumor targeting enabled by picomolar fibroblast activation protein inhibitors isolated from a DNA-encoded affinity maturation library

被引：22

作者：

Puglioli, Sara ^{[1
]}

Schmidt, Eleonore ^{[1
]}

Pellegrino, Christian ^{[2
,3
]}

Prati, Luca ^{[1
]}

Oehler, Sebastian ^{[1
]}

De Luca, Roberto ^{[1
]}

Galbiati, Andrea ^{[1
]}

Comacchio, Claudia ^{[5
]}

Nadal, Lisa ^{[1
]}

Scheuermann, Jorg ^{[4
]}

Manz, Markus G. ^{[2
,3
]}

Neri, Dari ^{[1
,4
]}

Cazzamalli, Samuele ^{[1
]}

Bassi, Gabriele ^{[1
]}

Favalli, Nicholas ^{[1
]}

机构：

[1] Philochem AG, R&D Dept, CH-8112 Zurich, Switzerland

[2] Univ Hosp Zurich, Dept Med Oncol & Hematol, CH-8091 Zurich, Switzerland

[3] Univ Zurich, CH-8091 Zurich, Switzerland

[4] Swiss Fed Inst Technol, Swiss Fed Inst Technol, Dept Chem & Appl Biosci, Zurich, Switzerland

[5] Swiss Fed Inst Technol, Swiss Fed Inst Technol, Dept Biol, Zurich, Switzerland

来源：

CHEM | 2023年 / 9卷 / 02期

关键词：

IN-VIVO; DISCOVERY; THERAPY; LIGANDS; BINDING; CANCER; FAP;

D O I：

10.1016/j.chempr.2022.10.006

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The availability of ultra-high-affinity small organic ligands, which are specific to accessible cancer antigens, is crucially important to enable efficient and selective tumor targeting applications. In this article, we describe the isolation of highly potent inhibitors of fibroblast activation protein (FAP), an enzyme that is abundantly and selectively expressed in the stroma of most of aggressive human solid malignancies. Affinity-maturation DNA-encoded chemical libraries, based on three series of 50,730 propargylglycine derivatives, enabled the identification of picomolar FAP inhibitors. A 177Lu-DOTAGA conjugate of the most potent novel ligand (named "OncoFAP-11'') localized to tumors implanted in mice, with tumor-to-blood ratios of similar to 220:1 17 h after intravenous administration. A dimeric derivative (named "BiOncoFAP-11'') further enhanced tumor residence time with a low uptake in healthy organs.

引用

页码：411 / 429

页数：20

共 46 条

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