Pharmacokinetics and dosimetry of radiolabeled FAP-targeting single-domain antibody 4AH29 in Göttingen minipigs

IF 3.1 4区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Nuclear medicine and biology Pub Date : 2026-07-01 Epub Date: 2026-06-25 DOI:10.1016/j.nucmedbio.2026.109654

Nina Dumauthioz, Laurent Navarro, Marion Berdal, Surasa Nagachinta, Jos Eersels, Vaiva Gaspariunaite, Ana Rita Pombo Antunes, Jonatan Dewulf, Sam Massa, Troels Jørgensen, Lotte Kellemann Kristensen, Trine Starostka, Dimitrios Mantzilas, Tony Lahoutte, Matthias. D'Huyvetter

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引用次数: 0

Abstract

Background

Fibroblast activation protein alpha (FAP) is a pan-tumor target highly expressed on cancer-associated fibroblasts. We developed 4AH29, a single-domain antibody binding FAP, and investigated the biodistribution of [¹³¹I]I-GMIB-4AH29 and [¹¹¹In]In-DOTA-4AH29 in Göttingen minipigs.

Methods

Following radiopharmaceutical administration, blood activity profile was determined by gamma-counter and biodistribution kinetics were determined using SPECT/CT imaging, respectively. The data obtained with [¹¹¹In]In-DOTA-4AH29 were used as a surrogate for its ¹⁷⁷Lu- and ²²⁵Ac-labeled analogues and extrapolation to human absorbed dose was calculated for all analogues.

Results

Radiolabeled 4AH29 showed good tolerability within the studied time frame. It displayed fast blood clearance driven by renal excretion. Kidney clearance dynamics of [¹³¹I]I-GMIB-4AH29 and [¹¹¹In]In-DOTA-4AH29 were distinct, likely driven by the different radiolabeling chemistry for halogen or metal conjugation. However, the contrasting patterns did not translate into relevant differences in mean residence time (MRT), nor was there a significant difference in bone marrow or liver MRTs when comparing halogen and metal-radiolabeled 4AH29. Extrapolated human absorbed doses for [¹³¹I]I-GMIB-4AH29 and [¹⁷⁷Lu]Lu-DOTA-4AH29 were compared given their similar particle decay and comparable physical half-lives. In kidneys, [¹³¹I]I-GMIB-4AH29 led to an extrapolated human absorbed dose of 8.23E-01 mGy/MBq, whereas [¹⁷⁷Lu]Lu-DOTA-4AH29 reached 5.86E-01 mGy/MBq. Consequently, the maximum tolerable administered activities were 28 and 39 GBq, respectively, to reach the renal absorbed dose limit of 23 Gy as determined by external beam radiation therapy (EBRT). In red marrow, the equivalent dose for [¹³¹I]I-GMIB-4AH29 was 3.8E-02 mGy/MBq and 1.36E-02 mGy/MBq with [¹⁷⁷Lu]Lu-DOTA-4AH29. Thus, 53 GBq and 148 GBq can be administered, respectively, before reaching the EBRT set absorbed dose threshold of 2 Gy.

Conclusion

4AH29 radiolabeled with ¹³¹I or ¹¹¹In is well tolerated in Göttingen minipigs within the studied time frame. Extrapolated dosimetry of radiolabeled 4AH29 using OLINDA software indicates that its administration within a clinically relevant range is possible without exceeding toxicity limits in critical organs.

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放射性标记fap靶向单域抗体4AH29在Göttingen迷你猪体内的药代动力学和剂量学研究。

背景：成纤维细胞活化蛋白（FAP）是一种泛肿瘤靶点，在癌症相关成纤维细胞中高度表达。我们开发了一种结合FAP的单域抗体4AH29，并研究了[131I] i - gmb -4AH29和[111In] in - dota -4AH29在Göttingen迷你猪中的生物分布。方法：放射性药物给药后，分别用伽马计数器测定血液活性谱，用SPECT/CT成像测定生物分布动力学。用[111In]In-DOTA-4AH29获得的数据作为其177Lu-和225ac标记的类似物的替代物，并计算所有类似物对人体吸收剂量的外推。结果：放射性标记的4AH29在研究时间内表现出良好的耐受性。它表现出由肾脏排泄驱动的快速血液清除。[131I] i - gmb - 4ah29和[111In]In-DOTA-4AH29的肾脏清除动力学是不同的，可能是由于卤素或金属偶联的放射性标记化学不同。然而，当比较卤素和金属放射性标记的4AH29时，对比模式并没有转化为平均停留时间（MRT）的相关差异，骨髓或肝脏MRT也没有显着差异。比较了[131I] i - gmb - 4ah29和[177Lu]Lu-DOTA-4AH29的外推人体吸收剂量，因为它们具有相似的粒子衰变和相似的物理半衰期。在肾脏中，[131I] i - gmb - 4ah29导致外推的人体吸收剂量为8.23E-01 mGy/MBq，而[177Lu]Lu-DOTA-4AH29达到5.86E-01 mGy/MBq。因此，最大耐受给药活性分别为28和39 GBq，以达到23 Gy的肾吸收剂量限值，由外部束放射治疗（EBRT）确定。在红骨髓中，[131I] i - gmb - 4ah29与[177Lu]Lu-DOTA-4AH29的等效剂量分别为3.8E-02 mGy/MBq和1.36E-02 mGy/MBq。因此，在达到EBRT设定的2 Gy的吸收剂量阈值之前，分别可以给药53 GBq和148 GBq。结论：131I或111In放射性标记的4AH29在研究时间内对Göttingen小型猪具有良好的耐受性。使用OLINDA软件对放射性标记的4AH29进行外推剂量测定表明，在临床相关范围内给药是可能的，而不会超过关键器官的毒性限值。

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来源期刊

Nuclear medicine and biology 医学-核医学

CiteScore

6.00

自引率

9.70%

发文量

479

审稿时长

51 days

期刊介绍： Nuclear Medicine and Biology publishes original research addressing all aspects of radiopharmaceutical science: synthesis, in vitro and ex vivo studies, in vivo biodistribution by dissection or imaging, radiopharmacology, radiopharmacy, and translational clinical studies of new targeted radiotracers. The importance of the target to an unmet clinical need should be the first consideration. If the synthesis of a new radiopharmaceutical is submitted without in vitro or in vivo data, then the uniqueness of the chemistry must be emphasized. These multidisciplinary studies should validate the mechanism of localization whether the probe is based on binding to a receptor, enzyme, tumor antigen, or another well-defined target. The studies should be aimed at evaluating how the chemical and radiopharmaceutical properties affect pharmacokinetics, pharmacodynamics, or therapeutic efficacy. Ideally, the study would address the sensitivity of the probe to changes in disease or treatment, although studies validating mechanism alone are acceptable. Radiopharmacy practice, addressing the issues of preparation, automation, quality control, dispensing, and regulations applicable to qualification and administration of radiopharmaceuticals to humans, is an important aspect of the developmental process, but only if the study has a significant impact on the field. Contributions on the subject of therapeutic radiopharmaceuticals also are appropriate provided that the specificity of labeled compound localization and therapeutic effect have been addressed.