Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Key Laboratory of Biological Nanotechnology of National Health Commission, Changsha, Hunan, China.
J Immunother Cancer. 2024 Jul 25;12(7):e009153. doi: 10.1136/jitc-2024-009153.
Lymphocyte activation gene 3 (LAG-3) has been considered as the next generation of immune checkpoint and a promising prognostic biomarker of immunotherapy. As with programmed cell death protein-1/programmed death-ligand 1 and cytotoxic T-lymphocyte antigen-4 inhibitors, positron emission tomography (PET) imaging strategies could benefit the development of clinical decision-making of LAG-3-related therapy. In this study, we developed and validated Ga-labeled cyclic peptides tracers for PET imaging of LAG-3 expression in bench-to-bedside studies.
A series of LAG-3-targeted cyclic peptides were modified and radiolabeled with GaCl and evaluated their affinity and specificity, biodistribution, pharmacokinetics, and radiation dosimetry in vitro and in vivo. Furthermore, hu-PBL-SCID (PBL) mice models were constructed to validate the capacity of [Ga]Ga-CC09-1 for mapping of LAG-3 lymphocytes infiltrates using longitudinal PET imaging. Lastly, [Ga]Ga-CC09-1 was translated into the first-in-human studies to assess its safety, biodistribution and potential for imaging of LAG-3 expression.
A series of cyclic peptides targeting LAG-3 were employed as lead compounds to design and develop Ga-labeled PET tracers. In vitro binding assays showed higher affinity and specificity of [Ga]Ga-CC09-1 in Chinese hamster ovary-human LAG-3 cells and peripheral blood mononuclear cells. In vivo PET imaging demonstrated better imaging capacity of [Ga]Ga-CC09-1 with a higher tumor uptake of 1.35±0.33 per cent injected dose per gram and tumor-to-muscle ratio of 17.18±3.20 at 60 min post-injection. Furthermore, [Ga]Ga-CC09-1 could detect the LAG-3 lymphocyte infiltrates in spleen, lung and salivary gland of PBL mice. In patients with melanoma and non-small cell lung cancer, primary lesions with modest tumor uptake were observed in [Ga]Ga-CC09-1 PET, as compared with that of [F]FDG PET. More importantly, [Ga]Ga-CC09-1 delineated the heterogeneity of LAG-3 expression within large tumors.
These findings consolidated that [Ga]Ga-CC09-1 is a promising PET tracer for quantifying the LAG-3 expression in tumor microenvironment, indicating its potential as a companion diagnostic for patients stratification and therapeutic response monitoring in anti-LAG-3 therapy.
淋巴细胞激活基因 3（LAG-3）被认为是下一代免疫检查点，也是免疫治疗的有前途的预后生物标志物。与程序性细胞死亡蛋白 1/程序性死亡配体 1 和细胞毒性 T 淋巴细胞抗原 4 抑制剂一样，正电子发射断层扫描（PET）成像策略可以帮助制定 LAG-3 相关治疗的临床决策。在这项研究中，我们开发并验证了 Ga 标记的环状肽示踪剂，用于临床前到临床的 LAG-3 表达的 PET 成像。
一系列靶向 LAG-3 的环状肽经过修饰并用 GaCl 放射性标记，并在体外和体内评估其亲和力和特异性、生物分布、药代动力学和辐射剂量学。此外，构建了 hu-PBL-SCID（PBL）小鼠模型，使用纵向 PET 成像验证 [Ga]Ga-CC09-1 用于定位 LAG-3 淋巴细胞浸润的能力。最后，将 [Ga]Ga-CC09-1 转化为首例人体研究，以评估其安全性、生物分布和 LAG-3 表达成像的潜力。
一系列靶向 LAG-3 的环状肽被用作设计和开发 Ga 标记的 PET 示踪剂的先导化合物。体外结合实验显示，[Ga]Ga-CC09-1 对中国仓鼠卵巢-人 LAG-3 细胞和外周血单核细胞具有更高的亲和力和特异性。体内 PET 成像显示，[Ga]Ga-CC09-1 具有更好的成像能力，肿瘤摄取率为每克 1.35±0.33 注射剂量百分比，肿瘤与肌肉的比值为 17.18±3.20，在注射后 60 分钟。此外，[Ga]Ga-CC09-1 可检测 PBL 小鼠脾脏、肺和唾液腺中的 LAG-3 淋巴细胞浸润。在患有黑色素瘤和非小细胞肺癌的患者中，与 [F]FDG PET 相比，[Ga]Ga-CC09-1 PET 观察到原发性病变的肿瘤摄取适度。更重要的是，[Ga]Ga-CC09-1 描绘了大肿瘤内 LAG-3 表达的异质性。
这些发现证实了 [Ga]Ga-CC09-1 是一种很有前途的 PET 示踪剂，可用于定量肿瘤微环境中的 LAG-3 表达，表明其作为抗 LAG-3 治疗患者分层和治疗反应监测的伴随诊断的潜力。
