177 Lu-NNS309

[177Lu]Lu-NNS309 (development code FXX489) is an investigational radioligand therapy built from the DOTA-chelated peptide NNS309 labelled with the beta-emitting radionuclide lutetium-177. It is designed to deliver targeted radiation to fibroblast activation protein (FAP)-expressing cancer-associated fibroblasts within advanced solid tumours, while a gallium-68 version of the same peptide ([68Ga]Ga-NNS309) is being developed as a companion PET diagnostic. Novartis opened a first-in-human phase 1 trial (NCT06562192) in October 2024 covering pancreatic, lung, breast and colorectal cancers, and the trial was still recruiting across 34 sites in 10 countries as of July 2026. The lutetium-177 isotope has a physical half-life of 6.7 days, which sets both the dosing interval and the dosimetry schedule. No regulatory authority has approved the compound, and it remains in early clinical development.[177Lu]Lu-NNS309（研发代号 FXX489）是一种在研放射配体疗法，由经 DOTA（四氮杂环十二烷四乙酸）螯合的多肽 NNS309 与发射 β 射线的放射性核素镥-177 标记而成。它设计用于向晚期实体瘤中表达成纤维细胞激活蛋白（FAP）的癌症相关成纤维细胞递送靶向辐射，同一多肽的镓-68 标记版本（[68Ga]Ga-NNS309）则作为伴随 PET 诊断剂开发。诺华于 2024 年 10 月启动覆盖胰腺癌、肺癌、乳腺癌与结直肠癌的首次人体 1 期试验（NCT06562192），截至 2026 年 7 月该试验仍在 10 个国家的 34 家中心招募患者。镥-177 的物理半衰期为 6.7 天，这决定了给药间隔与剂量学评估安排。该化合物未获任何监管机构批准，仍处于早期临床开发阶段。

History and development

• FAP is a type II transmembrane serine protease expressed on cancer-associated fibroblasts in many epithelial tumours, with minimal expression in most normal adult tissues, which makes it an attractive stromal target for radioligand therapy. The protein was cloned in 1994 as fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Mice genetically lacking FAP are viable and develop without gross abnormality, consistent with the low normal-tissue expression that underpins the therapeutic window. Early FAP-targeting radioligands suffered from high kidney uptake, so the NNS309 peptide was optimized using mRNA display selection together with FAP co-crystal structures to raise tumour retention and improve the tumour-to-kidney ratio. The selected peptide binds human and mouse FAP with sub-10-picomolar affinity and shows high selectivity over DPP4, its closest protease homologue. The peptide carries a DOTA chelator so that the same molecule can be labelled with gallium-68 for PET imaging or lutetium-177 for therapy, the basis of a theranostic pair.FAP 是一种 II 型跨膜丝氨酸蛋白酶，表达于多种上皮性肿瘤的癌症相关成纤维细胞，而在大多数正常成人组织中表达极低，因此成为放射配体疗法颇具吸引力的间质靶点。该蛋白于 1994 年被克隆为成纤维细胞激活蛋白 α，属于在上皮癌间质成纤维细胞中选择性表达的丝氨酸蛋白酶家族成员。基因敲除 FAP 的小鼠存活且无明显发育异常，与支撑治疗窗的低正常组织表达一致。早期 FAP 靶向放射配体存在肾脏摄取高的问题，NNS309 多肽因此借助 mRNA 展示筛选并结合 FAP 共晶结构进行优化，以提高肿瘤滞留并改善肿瘤与肾脏的摄取比。该多肽以低于 10 皮摩尔的亲和力结合人源与鼠源 FAP，并对其最接近的蛋白酶同源物 DPP4 表现出高选择性。多肽携带 DOTA 螯合剂，使同一分子既可用镓-68 标记用于 PET 显像，也可用镥-177 标记用于治疗，这正是诊疗一体化配对设计的基础。^[1]
• Small-molecule FAP inhibitors (FAPI) entered the clinic as PET tracers in 2018 and demonstrated high tumour uptake across dozens of cancer types, which motivated the development of therapeutic FAP radioligands carrying beta emitters such as lutetium-177. The theranostic blueprint had been validated commercially by PSMA-directed agents, culminating in the 2022 regulatory approval of the lutetium-177 labelled PSMA ligand [177Lu]Lu-PSMA-617 for metastatic castration-resistant prostate cancer. FAP offers a stromal rather than a tumour-cell target, so in principle one agent can address many tumour types that share a desmoplastic stroma. Novartis built the NNS309 programme on this logic, pairing the peptide with a gallium-68 diagnostic isotopologue from the outset.小分子 FAP 抑制剂（FAPI）于 2018 年作为 PET 示踪剂进入临床，在数十种癌症类型中显示高肿瘤摄取，这推动了携带 β 发射体（如镥-177）的治疗性 FAP 放射配体的开发。诊疗一体化蓝图此前已由 PSMA 靶向药物完成商业化验证，镥-177 标记的 PSMA 配体 [177Lu]Lu-PSMA-617 于 2022 年获批用于转移性去势抵抗性前列腺癌即其顶点。FAP 提供的是间质靶点而非肿瘤细胞靶点，因此原则上单一药物即可覆盖众多共享促纤维增生间质的肿瘤类型。诺华的 NNS309 项目即基于这一逻辑，从一开始就让该多肽与镓-68 诊断性同位素标记物配对。
• Novartis registered the first-in-human study CFXX489A12101 (NCT06562192) as a phase 1, open-label, multicentre trial combining dose escalation with dose expansion, and the first patient started treatment on 15 October 2024. Planned enrolment was initially reported as 124 patients and was later updated to 162 patients across 34 sites in 10 countries, with study completion estimated for June 2030 after a 36-month long-term follow-up period. The study record was last updated in July 2026 and recruitment was still ongoing at that point. The protocol was registered on ClinicalTrials.gov, the NIH-run trial registry that serves as the authoritative public record for the study design.诺华将首次人体研究 CFXX489A12101（NCT06562192）注册为 1 期、开放标签、多中心试验，采用剂量爬坡与剂量扩展相结合的设计，首例患者于 2024 年 10 月 15 日接受治疗。计划入组人数最初报告为 124 例，后更新为 10 个国家 34 家中心的 162 例，研究预计在 36 个月长期随访期之后的 2030 年 6 月完成。该研究记录最近一次更新为 2026 年 7 月，当时招募仍在进行。研究方案注册于 ClinicalTrials.gov，该 NIH 运营的试验注册库是研究设计的权威公开记录。
• The programme relies on centralized manufacturing: after a patient is confirmed eligible, the [177Lu]Lu-NNS309 dose is produced centrally and shipped to the participating centre. A companion imaging step with [68Ga]Ga-NNS309 PET/CT or PET/MRI precedes every treatment course, and only patients whose measurable lesions all show tracer uptake proceed to therapy. This theranostic workflow ties patient selection directly to target expression rather than to tumour type alone. The approach mirrors the broader radioligand field, in which a diagnostic isotopologue is used to verify target engagement before a therapeutic isotopologue is administered.该项目依赖集中化生产：患者资格确认后，[177Lu]Lu-NNS309 剂量经集中生产并配送至参与中心。每个疗程前均先行进行 [68Ga]Ga-NNS309 PET/CT 或 PET/MRI 伴随显像，只有全部可测量病灶均显示示踪剂摄取的患者才接受治疗。这一诊疗一体化工作流把患者选择直接与靶点表达挂钩，而非仅依据肿瘤类型。该策略与更广泛的放射配体领域一致，即在使用治疗性同位素标记物之前，先用诊断性同位素标记物验证靶点接合。
• Targeting the tumour stroma rather than the malignant cells themselves was proposed as a general oncology strategy in a 2019 review that framed cancer-associated fibroblasts as foes to be turned into friends, and FAP became the most clinically advanced stromal target in radioligand therapy. The FAP-targeting field has since produced several competing clinical candidates, the most advanced being FAP-2286, a cyclic FAP-binding peptide linked to DOTA that is also developed as a gallium-68 and lutetium-177 theranostic pair. FAP-2286 showed tumour retention of at least 72 hours in preclinical models, roughly triple that of the earlier FAPI-46 imaging agent, and entered first-in-human therapy testing in 2021.2019 年的一篇综述提出把肿瘤间质而非恶性细胞本身作为通用抗癌策略，将癌症相关成纤维细胞视为可化敌为友的对象，FAP 由此成为放射配体疗法中临床进展最快的间质靶点。FAP 靶向领域此后产出多个竞品临床候选药物，最成熟的是 FAP-2286——一种与 DOTA 连接的环状 FAP 结合多肽，同样按镓-68 与镥-177 诊疗配对开发。FAP-2286 在临床前模型中显示至少 72 小时的肿瘤滞留，约为早期显像剂 FAPI-46 的三倍，并于 2021 年进入首次人体治疗测试。

Medical uses

• No indication has been approved in any jurisdiction, and all use is confined to the phase 1 trial. The trial is enrolling adults aged 18 years or older with locally advanced unresectable or metastatic pancreatic ductal adenocarcinoma (PDAC) that has progressed after, or is intolerant to, cytotoxic chemotherapy. Further cohorts cover non-small cell lung cancer (NSCLC) without actionable genomic alterations after chemotherapy and immunotherapy, or with actionable alterations after targeted therapy. HR-positive/HER2-negative ductal or lobular breast cancer and triple-negative breast cancer are eligible after at least two prior lines of therapy, and colorectal cancer (CRC) is eligible after cytotoxic chemotherapy, with microsatellite instability-high or mismatch repair-deficient disease also requiring prior checkpoint inhibitor exposure.该化合物未在任何司法管辖区获批，全部使用仅限于 1 期试验。试验纳入 18 岁及以上、局部晚期不可切除或转移性胰腺导管腺癌（PDAC）且细胞毒化疗后进展或不耐受的成人患者。其他队列覆盖无可干预基因组改变、化疗与免疫治疗后进展的非小细胞肺癌（NSCLC），或携带可干预基因改变、靶向治疗后进展的 NSCLC。HR 阳性/HER2 阴性导管或小叶乳腺癌与三阴性乳腺癌需既往至少两线治疗失败，结直肠癌（CRC）需细胞毒化疗后进展，微卫星高度不稳定或错配修复缺陷者还需既往免疫检查点抑制剂暴露。
• Key laboratory entry criteria include an absolute neutrophil count of at least 1.5 x 10^9/L, haemoglobin of at least 9 g/dL, platelets of at least 100 x 10^9/L, a calculated glomerular filtration rate of at least 60 mL/min/1.73 m2, and a QTcF interval below 470 ms. Patients with unmanageable urinary tract obstruction or urinary incontinence are excluded, as is prior radiotherapy within 4 weeks of the first dose. All patients must show measurable [68Ga]Ga-NNS309 uptake on screening PET, so target expression rather than histology alone drives eligibility.关键实验室入组标准包括绝对中性粒细胞计数至少 1.5 x 10^9/L、血红蛋白至少 9 g/dL、血小板至少 100 x 10^9/L、肌酐清除率至少 60 mL/min/1.73 m2，以及 QTcF 间期低于 470 ms。不可控的尿路梗阻或尿失禁患者排除，首次给药前 4 周内接受过放疗者亦排除。所有患者必须在筛选 PET 上显示可测量的 [68Ga]Ga-NNS309 摄取，因此靶点表达而非组织学单独决定入选。
• Because the agent is still in dose escalation, there is no recommended phase 2 dose, no established line of therapy, and no use in special populations such as children or pregnant women. Any statement about efficacy remains preliminary, and no overall response rate or disease control rate has been published for [177Lu]Lu-NNS309. The trial's primary endpoints are dose modifications, with secondary endpoints covering dosimetry and preliminary antitumour activity.由于该药仍处于剂量爬坡阶段，尚无推荐 2 期剂量、既定治疗线数，亦无儿童或妊娠人群使用数据。任何疗效表述均为初步，[177Lu]Lu-NNS309 的客观缓解率或疾病控制率尚未公布。试验主要终点为剂量调整，次要终点包括剂量学与初步抗肿瘤活性。
• Access outside the protocol does not exist: there is no expanded-access or compassionate-use programme for the compound, and it is not licensed to any commercial supplier, so the only route of administration is enrolment in the registered trial. Patients who progress on screening PET are offered standard-of-care options at the participating centre. The four tumour cohorts were chosen for stromal richness and unmet need rather than for a biomarker-selected population, so FAP expression is confirmed per patient by the companion scan.方案之外不存在可及性途径：该化合物没有扩大可及或同情使用项目，也未授权任何商业供应商，因此唯一的给药途径是入组注册试验。筛选 PET 上出现进展的患者在参与中心接受标准治疗方案。四个肿瘤队列的选择依据是间质富集程度与未满足需求，而非生物标志物筛选人群，因此 FAP 表达由伴随扫描逐例确认。
• The companion diagnostic itself has potential beyond patient selection: serial [68Ga]Ga-NNS309 PET scans can quantify target expression across lesions and over time, which the protocol uses to build patient-specific dosimetry models. In the broader field, imaging-based dosimetry has become the standard method for planning radioligand therapy, replacing fixed-dose schemes at several centres. If the therapy is approved in future, the same peptide would allow treatment monitoring by imaging rather than by biopsy.伴随诊断剂的潜力不止于患者筛选：连续 [68Ga]Ga-NNS309 PET 扫描可量化各病灶及不同时间点的靶点表达，方案借此构建患者个体化剂量学模型。在更广的领域内，基于显像的剂量学已成为放射配体疗法的标准计划方法，在多家中心取代固定剂量方案。若该疗法将来获批，同一多肽即可通过显像而非活检监测治疗反应。

Adverse effects

• No adverse-event profile has been published for [177Lu]Lu-NNS309, because the first-in-human study is still in dose escalation and interim safety data have not been disclosed. The trial's stated purpose is to evaluate safety, tolerability, dosimetry and preliminary activity, so adverse-effect rates cannot yet be quantified. Investigational FAP-targeted radioligands as a class are monitored for haematologic, renal and radiation-specific toxicities, but class-level experience must not be read as established safety data for this compound.[177Lu]Lu-NNS309 的不良反应谱尚未公布，因为首次人体研究仍处于剂量爬坡阶段，中期安全性数据未披露。试验既定目的是评估安全性、耐受性、剂量学与初步活性，因此尚不能量化不良反应发生率。在研的 FAP 靶向放射配体作为一类药物通常监测血液学、肾脏与辐射特异性毒性，但类经验不能读作该化合物已确立的安全性数据。
• Class experience from the most advanced FAP radioligand gives a sense of the expected profile: in the first-in-human series of [177Lu]Lu-FAP-2286 in 11 patients, there were no grade 4 events, and grade 3 events occurred in three patients, one each with pancytopenia, leukocytopenia and a pain flare-up. Haematologic and renal toxicity are the dose-limiting organs for this class because the peptides are cleared through the kidneys. Whether the NNS309 peptide's improved tumour-to-kidney ratio translates into a wider margin can only be judged once dosimetry data are reported.最成熟的 FAP 放射配体的类经验可提示预期毒性谱：在 [177Lu]Lu-FAP-2286 的 11 例首次人体系列中无 4 级事件，3 级事件发生于 3 例患者，分别为全血细胞减少、白细胞减少与疼痛突发各一例。血液学与肾脏毒性是该类药物的剂量限制器官，因为多肽经肾脏清除。NNS309 多肽改善的肿瘤肾脏摄取比能否转化为更宽的治疗窗，只有待剂量学数据报告后才能判断。^[2]
• The protocol's exclusion thresholds function as a de facto safety framework: bone marrow reserve is protected through the neutrophil, haemoglobin and platelet cut-offs, and renal function is protected through the glomerular filtration rate floor and the exclusion of urinary tract obstruction. Patients may be required to stay overnight in hospital on days with intensive assessment schedules, such as dosimetry blood sampling, as a radiation-protection measure. These logistics reflect the radionuclide's radiation safety requirements rather than a pharmacological contraindication.方案的排除阈值事实上构成安全框架：通过中性粒细胞、血红蛋白与血小板界值保护骨髓储备，通过肌酐清除率下限与尿路梗阻排除保护肾功能。在评估密集的日期（如剂量学采血日），患者可能被要求在医院留宿一晚，作为辐射防护措施。这些安排源于放射性核素的辐射安全要求，而非药理学禁忌。
• Lutetium-177 emits both therapeutic beta particles and imageable gamma photons, which makes it possible to verify the delivered distribution after administration with a gamma camera. Because the gamma abundance is modest, the radiation-protection burden for caregivers is lower than for high-gamma emitters, and most centres treat lutetium-177 therapies on an outpatient basis. The absorbed dose to red marrow remains the principal haematologic constraint, and dosimetry sampling in the protocol is designed to keep it within accepted limits for peptide radioligand therapy.镥-177 同时发射治疗性 β 粒子与可显像的 γ 光子，因此可在给药后用 γ 相机验证实际分布。由于 γ 丰度有限，对陪护人员的辐射防护负担低于高 γ 发射体，多数中心按门诊方式实施镥-177 治疗。红骨髓的吸收剂量仍是主要血液学约束，方案中的剂量学采样旨在使其保持在多肽放射配体疗法的公认限值内。

Contraindications and interactions

• Formal contraindications have not been established for an investigational agent with no approved label, and the phase 1 protocol lists exclusions rather than contraindications. Absolute exclusions include a QTcF of 470 ms or longer, radiation therapy within 4 weeks before the first dose, and unmanageable urinary tract obstruction or incontinence. Protocol-defined laboratory thresholds further restrict enrolment when marrow or renal reserve is inadequate. No food or beverage interaction has been reported for the compound.对于无获批标签的在研药物，正式禁忌尚未确立，1 期方案列出的是排除标准而非禁忌。绝对排除包括 QTcF 达到或超过 470 ms、首次给药前 4 周内接受放疗、不可控的尿路梗阻或尿失禁。当骨髓或肾脏储备不足时，方案定义的实验室界值进一步限制入组。尚无该化合物食物或饮料相互作用的报告。
• No drug-interaction study has been published, and the peptide is expected to be cleared renally as a radioligand, although formal excretion data remain proprietary. The exclusion of prior radiotherapy within 4 weeks is intended to avoid overlapping normal-tissue radiation exposure rather than to reflect a metabolic interaction. Until interaction data emerge, concomitant nephrotoxic or myelosuppressive agents are managed under trial-specific rules.尚无药物相互作用研究发表，该多肽作为放射配体预计经肾清除，但正式排泄数据仍未公开。排除 4 周内放疗是为了避免正常组织辐射暴露叠加，而非反映代谢性相互作用。在相互作用数据出现之前，合并肾毒性或骨髓抑制药物按试验特定规则管理。
• As with other radioligand therapies, pregnancy and lactation are handled as protocol exclusions rather than as label contraindications, because ionizing radiation poses fetal and infant risk. Patients of childbearing potential must use contraception during the study and for a defined period after the last dose. Because the compound is given intravenously in a controlled setting, food and beverage interactions of the kind seen with oral small molecules are not expected, and none have been described for the class.与其他放射配体疗法一样，妊娠与哺乳按方案排除标准处理而非标签禁忌，因为电离辐射对胎儿与婴儿构成风险。育龄期受试者须在研究期间及末次给药后规定期限内采取避孕措施。由于该化合物在受控环境下静脉给药，口服小分子所见的那类食物饮料相互作用不构成预期，类内亦无描述。

Pharmacology

• The pharmacological target is FAP, a serine protease displayed on cancer-associated fibroblasts that build the tumour stroma of many epithelial cancers. Lutetium-177 emits beta particles with a maximum energy of about 0.5 MeV and a physical half-life of 6.647 days, giving a short tissue range that concentrates absorbed dose in FAP-expressing stromal cells while a cross-fire effect damages adjacent tumour cells. Because the target sits in the stroma rather than on the tumour cell itself, the therapeutic effect is indirect and is being tested across four tumour types. Binding studies report sub-10-picomolar affinity for human and mouse FAP with selectivity over DPP4.药理学靶点是 FAP，一种展示于癌症相关成纤维细胞表面的丝氨酸蛋白酶，此类细胞构成多种上皮性肿瘤的间质。镥-177 发射最大能量约 0.5 MeV 的 β 粒子，物理半衰期 6.647 天，组织射程短，使吸收剂量集中于表达 FAP 的间质细胞，同时以交叉火力效应损伤相邻肿瘤细胞。由于靶点位于间质而非肿瘤细胞表面，治疗效果是间接的，目前正在四种肿瘤类型中检验。结合研究报告其对人与小鼠 FAP 的亲和力低于 10 皮摩尔，并对 DPP4 有选择性。
• The decay scheme of lutetium-177 combines beta emissions at maximum energies of 0.497, 0.384 and 0.176 MeV with gamma photons at 208 and 113 keV, the latter enabling post-therapy imaging for verification. The mean beta tissue range of roughly 0.2 mm with a maximum near 2 mm is short enough to spare tissue beyond the immediate microenvironment, which is the physical basis for the stromal cross-fire concept. The 6.7-day physical half-life supports dosing intervals of several weeks, and it also gives radiopharmacy sites a workable shipping window from central production.镥-177 的衰变方式包括最大能量 0.497、0.384 与 0.176 MeV 的 β 发射，以及 208 与 113 keV 的 γ 光子，后者使治疗后验证显像成为可能。β 平均组织射程约 0.2 毫米、最大接近 2 毫米，短到足以豁免直接微环境以外的组织，这正是间质交叉火力概念的物理基础。6.7 天的物理半衰期支持数周一次的给药间隔，也为放射药房站点提供了从集中生产发货的可行运输窗口。
• Pharmacokinetics are governed by the radionuclide as much as by the peptide: the 6.7-day physical half-life of lutetium-177 supports dosing intervals of several weeks, and serial blood sampling is used to build patient-specific dosimetry models. The peptide component was selected for improved tumour retention and a higher tumour-to-kidney ratio than earlier FAP ligands, addressing the renal dosimetry that limits this class. Distribution, metabolism and excretion data for the peptide itself have not been published, and the compound is administered intravenously. Renal handling is the critical unknown because FAP ligands of this type are cleared through the kidneys.药代动力学在很大程度上由放射性核素而非仅由多肽决定：镥-177 6.7 天的物理半衰期支持数周一次的给药间隔，系列采血用于构建患者个体化剂量学模型。多肽组分经筛选获得优于早期 FAP 配体的肿瘤滞留与更高肿瘤肾脏摄取比，针对的正是限制这一类药物上市的肾脏剂量学问题。多肽本身的分布、代谢与排泄数据尚未发表，给药途径为静脉注射。肾脏处置是关键未知项，因为此类 FAP 配体经肾脏清除。
• Benchmark dosimetry for the class comes from the first-in-human [177Lu]Lu-FAP-2286 study, which reported mean absorbed doses of 1.0 plus or minus 0.6 Gy/GBq to the kidneys and 0.05 plus or minus 0.02 Gy/GBq to red marrow, with whole-body effective dose of 0.07 plus or minus 0.02 Gy/GBq and tumour doses up to 3.0 plus or minus 2.7 Gy/GBq in bone metastases. Those numbers illustrate why renal dosimetry drives schedule design for stromal radioligands and why marrow tolerance sets the ceiling on administered activity. A peptide with a higher tumour-to-kidney ratio could shift that balance, but head-to-head data do not exist.该类的基准剂量学来自 [177Lu]Lu-FAP-2286 的首次人体研究，其报告肾脏平均吸收剂量为每 GBq 1.0 加减 0.6 Gy、红骨髓为每 GBq 0.05 加减 0.02 Gy，全身有效剂量为每 GBq 0.07 加减 0.02 Gy，骨转移灶剂量最高达每 GBq 3.0 加减 2.7 Gy。这些数字说明肾脏剂量学为何主导间质放射配体的方案设计，也说明骨髓耐受为何设定给药活度的上限。肿瘤肾脏摄取比更高的多肽可能改变这一平衡，但目前不存在头对头数据。^[2]
• The diagnostic isotopologue [68Ga]Ga-NNS309 serves a pharmacological as well as a logistical role: PET uptake is used both to confirm eligibility and to estimate target expression across lesions. In theranostic terms, the pair shares an identical targeting vector and differs only in the radionuclide, so imaging-based dosimetry can be transferred to therapy planning. This selection strategy contrasts with tumour-agnostic approaches and concentrates treatment on patients whose stroma actually expresses the target.诊断性同位素标记物 [68Ga]Ga-NNS309 兼具药理学与流程意义：PET 摄取既用于确认入选，也用于评估各病灶的靶点表达。按诊疗一体化术语，该配对共享相同的靶向载体、仅放射性核素不同，因此基于显像的剂量学可转移至治疗计划。该选择策略与不区分瘤种的做法相反，把治疗集中于间质确实表达靶点的患者。
• Pharmacodynamic readouts for stromal radioligands differ from those of tumour-cell agents: instead of tumour shrinkage as the first signal, programmes in this class watch absorbed dose to stromal cells, changes in FAP expression on serial PET, and delayed tumour responses. The cross-fire design means that cells that never bind the peptide can still be damaged if they sit close to a targeted fibroblast, an effect that is central to the stroma-directed rationale but hard to verify without dosimetry. No pharmacodynamic marker for [177Lu]Lu-NNS309 has been validated to date.间质放射配体的药效学读数不同于肿瘤细胞药物：该类项目关注的第一个信号不是肿瘤缩小，而是间质细胞的吸收剂量、连续 PET 上 FAP 表达的变化以及延迟出现的肿瘤反应。交叉火力设计意味着从未结合多肽的细胞若紧邻靶向成纤维细胞也可受损，这一效应对间质靶向原理至关重要，但离开剂量学难以验证。迄今尚无 [177Lu]Lu-NNS309 的经验证药效学标志物。

Chemistry

• NNS309 is a cyclic peptide conjugated to a DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) chelator that stably complexes lutetium-177 or gallium-68. The peptide has molecular formula C89H128N20O25 and InChIKey NIMFRTFOYUYZQS-JXPRPOKFSA-N, and the radiolabelled product carries one lutetium-177 ion per peptide. The cyclic constraint and the chelator placement were both shaped by the mRNA display selection process, which favored sequences with high FAP affinity and favourable clearance. The DOTA chelate is the standard choice for trivalent lanthanides and gives the complex the kinetic stability required for a multi-day half-life radionuclide.NNS309 是一种与 DOTA（1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸）螯合剂缀合的环肽，可稳定螯合镥-177 或镓-68。该多肽分子式为 C89H128N20O25，InChIKey 为 NIMFRTFOYUYZQS-JXPRPOKFSA-N，放射性标记产物每个多肽携带一个镥-177 离子。环化约束与螯合剂位置均由 mRNA 展示筛选过程塑形，该过程偏爱具有高 FAP 亲和力与良好清除特性的序列。DOTA 螯合物是三价镧系元素的标准选择，赋予复合物半衰期数天的放射性核素所需的动力学稳定性。
• Structure-guided optimization used co-crystal structures of FAP with peptide ligands, so the tumour-retention gains came from rational design rather than from library screening alone. The optimized ligand shows high selectivity over DPP4, the closest protease homologue, reducing off-target radioligand accumulation in DPP4-expressing tissues. No salt forms or alternative chelator versions have been disclosed for the clinical candidate, and the chemical identity of the precursor peptide is registered in PubChem under CID 172991796. Formulation details of the clinical-grade radioligand have not been published.结构引导的优化利用了多肽配体与 FAP 的共晶结构，因此肿瘤滞留的提升来自理性设计而非单纯文库筛选。优化后的配体对最接近的蛋白酶同源物 DPP4 具有高选择性，减少在 DPP4 表达组织中的脱靶放射配体蓄积。临床候选药物尚未披露盐型或其他螯合剂版本，前体多肽的化学身份在 PubChem 注册号为 CID 172991796。临床级放射配体的处方细节尚未公布。
• Radiolabelling with lutetium-177 follows the standard DOTA chemistry: the peptide is incubated with the radionuclide in a buffered acidic medium at elevated temperature for tens of minutes, and the product is purified and quality-controlled by chromatographic methods before release. Radiochemical purity and specific activity are the critical release attributes, because free lutetium-177 accumulates in bone and would confound dosimetry. The unlabelled peptide precursor is catalogued as FXX489, and no cold-kit formulation has been disclosed.镥-177 的放射标记遵循标准 DOTA 化学：多肽与放射性核素在缓冲酸性介质中升温孵育数十分钟，产物经色谱方法纯化与质控后放行。放射化学纯度与比活度是关键放行属性，因为游离镥-177 会在骨中蓄积并干扰剂量学。未标记多肽前体登记代号为 FXX489，尚无冻干药盒处方披露。
• The competing FAP-2286 agent demonstrates the alternative design space for this class: a cyclic peptide with DOTA achieves tumour retention of at least 72 hours, roughly triple that of the earlier FAPI-46 agent, and the field has also tested NOTA and DOTAGA chelators that label at milder conditions. Chelator choice affects both the labelling yield and the in vivo stability, and DOTA remains the most validated option for multi-day beta emitters. Whether the NNS309 peptide ultimately shows superior retention to FAP-2286 is a central question for the programme, and no comparative data exist yet.竞品 FAP-2286 展示了该类药物的替代设计空间：环状多肽加 DOTA 实现至少 72 小时的肿瘤滞留，约为早期 FAPI-46 药物的三倍，该领域还测试了可在更温和条件下标记的 NOTA 与 DOTAGA 螯合剂。螯合剂选择同时影响标记产率与体内稳定性，DOTA 仍是多天 β 发射体经验证最多的选项。NNS309 多肽最终能否显示优于 FAP-2286 的滞留，是该项目的核心问题，目前尚无对比数据。

Society and culture

• The compound has no legal scheduling as a narcotic and is handled as a radioactive medicinal product under each country's radiopharmaceutical regulations rather than under drug-scheduling systems. It does not appear on the WHO Model List of Essential Medicines and has no ATC code, which is expected for a first-in-class investigational agent. The theranostic design has drawn attention as a template for FAP-directed programmes, in which imaging and therapy are co-developed from a single peptide scaffold. Public discussion has focused on the stromal-targeting concept, since most approved radioligand therapies such as those built on somatostatin or PSMA ligands target receptors on the tumour cell itself.该化合物无麻醉品法律列管，按各国放射性药品法规而非药品列管体系作为放射性药品管理。它未出现在 WHO 基本药物示范清单上，也没有 ATC 编码，这对首创在研药物属预期。诊疗一体化设计作为 FAP 靶向项目的模板受到关注，其中显像与治疗从同一多肽骨架共同开发。公众讨论聚焦于间质靶向概念，因为大多数已批准的放射配体疗法（如基于生长抑素或 PSMA 配体的疗法）靶向的是肿瘤细胞表面的受体。
• Stromal targeting has been promoted in the oncology literature as a way to attack the supportive tissue that most carcinomas build around themselves, with a 2019 review framing cancer-associated fibroblasts as foes to be turned into friends. Advocates argue that stromal targets are genetically more stable than tumour-cell targets and therefore less prone to escape by mutation, while critics counter that damaging stroma could impair drug delivery to the tumour itself. FAP-directed radioligand therapy has become the most clinically tested expression of that debate, with multiple agents in phase 1 and phase 2 trials.肿瘤学文献将间质靶向推广为攻击大多数癌种围绕自身构建的支持组织的方法，2019 年的一篇综述把癌症相关成纤维细胞视为可化敌为友的对象。支持者认为间质靶点在遗传上比肿瘤细胞靶点更稳定，因而不易因突变逃逸，批评者则反驳损伤间质可能削弱药物向肿瘤本身的递送。FAP 靶向放射配体疗法已成为这场争论临床检验最充分的表达，多个药物处于 1 期与 2 期试验中。^[3]
• As a radioactive medicinal product, the compound falls under national nuclear-medicine regulations that govern production, transport and disposal rather than under narcotics scheduling, and its handling requires licensed radiopharmacy facilities. Because it has no marketing authorization, no pricing, reimbursement or advertising rules apply, and trial sponsors carry the reporting obligations for radiation safety events. The compound's investigational status also means it appears in no national formulary and in no WHO essential-medicines list.作为放射性药品，该化合物受各国核医学法规对生产、运输与处置的管辖，而非麻醉品列管，其操作需要具备资质的放射药房设施。由于没有上市许可，不存在定价、报销或广告规则的适用，试验申办方承担辐射安全事件的报告义务。该化合物的在研身份也意味着它不出现在任何国家处方集与 WHO 基本药物名录中。

Availability and economics

• The compound is not commercially available anywhere and is supplied only through the clinical trial, with centralized manufacturing and shipment to participating centres. There is no list price, no reimbursement status and no generic or biosimilar landscape, because no market authorization exists. As of the July 2026 trial-record update, the study was running at 34 sites across 10 countries, with enrollment planned at 162 patients and completion estimated for June 2030. Access is therefore limited to trial participants at designated centres, principally in Europe and North America.该化合物在任何地方均无商业供应，仅通过临床试验提供，采用集中生产并配送至参与中心的方式。由于不存在市场授权，没有挂牌价格、没有报销状态，也没有仿制药或生物类似药格局。截至 2026 年 7 月试验记录更新，研究在 10 个国家的 34 家中心进行，计划入组 162 例，预计 2030 年 6 月完成。因此可及性仅限于指定中心（主要在欧美）的试验受试者。
• The economic case rests on the theranostic pair rather than on a single product, because the companion [68Ga]Ga-NNS309 diagnostic is expected to be co-developed and could be used to select patients for therapy. No pricing, cost-effectiveness or health-technology-assessment data exist for either agent. Development costs are being carried by Novartis, and the programme's fate will depend on phase 1 dosimetry and early activity readouts across the four tumour cohorts. Until such data are published, any market projection would be speculative.其经济依据建立在诊疗一体化配对而非单一产品上，因为伴随诊断 [68Ga]Ga-NNS309 预计将共同开发，并可能用于筛选治疗患者。两种药物均无定价、成本效果或卫生技术评估数据。开发成本由诺华承担，项目前途取决于 1 期在四个肿瘤队列中的剂量学与早期活性读数。在此类数据公布前，任何市场预测都是推测性的。
• Supply of lutetium-177 depends on reactor irradiation of enriched lutetium-176 targets, and the radionuclide is produced by a small number of facilities worldwide, which has made isotope availability a strategic concern for the whole radioligand field. The 6.7-day half-life is long enough to ship doses across continents but short enough to require tightly scheduled production, and competing programmes draw on the same constrained supply. Centralized manufacturing with shipment to trial sites, as used here, is the standard mitigation.镥-177 的供应依赖核反应堆辐照富集镥-176 靶件，全球生产设施数量有限，这使同位素可得性成为整个放射配体领域的战略性关切。6.7 天的半衰期长到足以跨洲运输剂量，又短到要求严密排产，相互竞争的项目争夺同一受限供应。本项目采用的集中生产并配送至试验站点，是标准的缓解方案。
• Competing FAP-directed agents are ahead in development: FAP-2286 has reached phase 2 testing in the LuMIERE programme after Novartis acquired the rights from 3B Pharmaceuticals following the bankruptcy of the original sponsor, and several academic [177Lu]Lu-FAPI programmes have reported phase 2 cohorts. If any of these reaches the market first, it would set the pricing and reimbursement precedent for the class, and [177Lu]Lu-NNS309 would enter as a later follower. For patients, the practical consequence today is that access is confined to the registered trial at a limited number of centres.竞品 FAP 靶向药物开发更为领先：FAP-2286 在原申办方破产后由诺华从 3B Pharmaceuticals 收购权益，现已进入 LuMIERE 项目的 2 期测试，另有多个学术性 [177Lu]Lu-FAPI 项目报告了 2 期队列。若其中任一药物率先上市，它将为该类设定定价与报销先例，[177Lu]Lu-NNS309 则以后来者身份进入。对患者而言，当前的实际结果是可及性仅限数量有限中心的注册试验。