Nehmé Rita, Fortier Marlène, Létourneau Myriam, Fuselier Camille, Granger Joly de Boissel Philippine, Dumoulin Alyssa, Guérin Brigitte, Dumulon-Perreault Véronique, Ait-Mohand Samia, Sarrhini Otman, Larda Sacha T, Castellanos Villamizar Yarileny, Bernier Mighel, Porębska Natalia, Opaliński Łukasz, Chatenet David, Doucet Nicolas, St-Pierre Yves
INRS─Centre Armand-Frappier Santé Biotechnologie, Laval, Québec H7 V 1B7, Canada.
Department of Medical Imaging and Radiation Sciences, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.
J Med Chem. 2025 Apr 24;68(8):8484-8496. doi: 10.1021/acs.jmedchem.5c00071. Epub 2025 Apr 10.
Galectins play significant roles in regulating immune responses, posing challenges for cancer immunotherapy. The development of galectin inhibitors has been limited by their high structural homology and the lack of noninvasive imaging tools to identify potential responsive patients. We developed 12 galectin-7-specific inhibitors using nanobodies (Nbs) and identified G7N8 as the lead Nb. G7N8 was conjugated with the NOTA chelator, labeled with copper-64 ([Cu]Cu), and used as a radiotracer for PET imaging in a triple-negative breast cancer (TNBC) mouse model. Nbs demonstrated high affinity for galectin-7, with no binding activity for other galectins tested. The lead Nbs inhibited galectin-7 binding to T-cell glycoreceptors and reduced subsequent apoptosis. PET imaging with [Cu]Cu-NOTA-G7N8 showed selective radiotracer accumulation at 20 h ( = 0.001). We developed galectin-7-specific Nbs that inhibit T-cell apoptosis and enable PET imaging of TNBC, providing novel tools for investigating immune regulation and enhancing cancer immunotherapy.
半乳凝素在调节免疫反应中发挥着重要作用，这给癌症免疫治疗带来了挑战。半乳凝素抑制剂的开发受到其高度结构同源性以及缺乏用于识别潜在反应性患者的非侵入性成像工具的限制。我们利用纳米抗体（Nb）开发了12种半乳凝素-7特异性抑制剂，并确定G7N8为主要的纳米抗体。G7N8与NOTA螯合剂偶联，用铜-64（[Cu]Cu）标记，并用作三阴性乳腺癌（TNBC）小鼠模型中PET成像的放射性示踪剂。纳米抗体对半乳凝素-7表现出高亲和力，对测试的其他半乳凝素无结合活性。主要的纳米抗体抑制半乳凝素-7与T细胞糖受体的结合，并减少随后的细胞凋亡。用[Cu]Cu-NOTA-G7N8进行的PET成像显示，在20小时时放射性示踪剂有选择性积聚（P = 0.001）。我们开发了抑制T细胞凋亡并能对TNBC进行PET成像的半乳凝素-7特异性纳米抗体，为研究免疫调节和增强癌症免疫治疗提供了新工具。
