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. 2021 Nov 24;14(12):1212.
doi: 10.3390/ph14121212.

First-In-Human Results on the Biodistribution, Pharmacokinetics, and Dosimetry of [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2

Sanjana Ballal  1 , Madhav Prasad Yadav  1 , Euy Sung Moon  2 , Vasko S Kramer  3 , Frank Roesch  2 , Samta Kumari  1 , Chandrasekhar Bal  1
Affiliations

First-In-Human Results on the Biodistribution, Pharmacokinetics, and Dosimetry of [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2

Sanjana Ballal et al. Pharmaceuticals (Basel). .

Abstract

Recently, great interest has been gained regarding fibroblast activation protein (FAP) as an excellent target for theranostics. Several FAP inhibitor molecules such as [68Ga]Ga-labelled FAPI-02, 04, 46, and DOTA.SA.FAPi have been introduced and are highly promising molecular targets from the imaging point of view. FAP inhibitors introduced via bifunctional DOTA and DOTAGA chelators offer the possibility to complex Lutetium-177 due to an additional coordination site, and are suitable for theranostic applications owing to the increased tumor accumulation and prolonged tumor retention time. However, for therapeutic applications, very little has been accomplished, mainly due to residence times of the compounds. In an attempt to develop a promising therapeutic radiopharmaceutical, the present study aimed to evaluate and compare the biodistribution, pharmacokinetics, and dosimetry of [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 in patients with various cancers. The FAPi agents, [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2, were administered in two different groups of patients. Three patients (mean age-50 years) were treated with a median cumulative activity of 2.96 GBq (IQR: 2.2-3 GBq) [177Lu]Lu-DOTA.SA.FAPi and seven (mean age-51 years) were treated with 1.48 GBq (IQR: 0.6-1.5) of [177Lu]Lu-DOTAGA.(SA.FAPi)2. Patients in both the groups underwent serial imaging whole-body planar and SPECT/CT scans that were acquired between 1 h and 168 h post-injection (p.i.). The residence time and absorbed dose estimate in the source organs and tumor were calculated using OLINDA/EXM 2.2 software. Time versus activity graphs were plotted to determine the effective half-life (Te) in the whole body and lesions for both the radiotracers. Physiological uptake of [177Lu]Lu-DOTA.SA.FAPi was observed in the kidneys, colon, pancreas, liver, gall bladder, oral mucosa, lacrimal glands, and urinary bladder contents. Physiological biodistribution of [177Lu]Lu-DOTAGA.(SA.FAPi)2 involved liver, gall bladder, colon, pancreas, kidneys, and urinary bladder contents, lacrimal glands, oral mucosa, and salivary glands. In the [177Lu]Lu-DOTA.SA.FAPi group, the highest absorbed doses were noted in the kidneys (0.618 ± 0.015 Gy/GBq), followed by the colon (right colon: 0.472 Gy/GBq and left colon: 0.430 Gy/GBq). In the [177Lu]Lu-DOTAGA.(SA.FAPi)2 group, the colon received the highest absorbed dose (right colon: 1.160 Gy/GBq and left colon: 2.870 Gy/GBq), and demonstrated a significantly higher mean absorbed dose than [177Lu]Lu-DOTA.SA.FAPi (p < 0.011). [177Lu]Lu-DOTAGA.(SA.FAPi)2 had significantly longer median whole-body Te compared to that of [177Lu]Lu-DOTA.SA.FAPi [46.2 h (IQR: 38.5-70.1) vs. 23.1 h (IQR: 17.8-31.5); p-0.0167]. The Te of tumor lesions was significantly higher for [177Lu]Lu-DOTAGA.(SA.FAPi)2 compared to [177Lu]Lu-DOTA.SA.FAPi [86.6 h (IQR: 34.3-94.6) vs. 14 h (IQR: 12.8-15.5); p-0.0004]. The median absorbed doses to the lesions were 0.603 (IQR: 0.230-1.810) Gy/GBq and 6.70 (IQR: 3.40-49) Gy/GBq dose per cycle in the [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 groups, respectively. The first clinical dosimetry study demonstrated significantly higher tumor absorbed doses with [177Lu]Lu-DOTAGA.(SA.FAPi)2 compared to [177Lu]Lu-DOTA.SA.FAPi. [177Lu]Lu-DOTAGA.(SA.FAPi)2 is safe and unveiled new frontiers to treat various end-stage cancer patients with a theranostic approach.

Keywords: [177Lu]Lu-DOTA.SA.FAPi; [177Lu]Lu-DOTAGA.(SA.FAPi)2; [68Ga]Ga-DOTA.SA.FAPi PET/CT; absorbed dose estimates; biodistribution; dosimetry; effective half-life; pharmacokinetics.

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Conflict of interest statement

All the authors included in this manuscript state no conflict of interest.

Figures

Figure 1
Figure 1
Generations of chelator–linker FAP inhibitor conjugates, a step towards development of FAP-targeted theranostics.
Figure 2
Figure 2
(a). [68Ga]Ga-DOTA.SA.FAPi PET/CT images of a 49-year-old woman with breast cancer shows biodistribution in the oral mucosa, pancreas, and kidneys and intense expression of DOTA.SA.FAPi in extensive skeletal metastases. B Serial [177Lu]Lu-DOTA.SA.FAPi whole body scintigraphy images for dosimetry, after intravenous injection of 1.85 GBq of radiotracer, demonstrates normal and minimal biodistribution in the oral mucosa, salivary glands, liver, kidneys, and intestines. (b). Accumulation in the metastatic sites were observed at 1 and 6 h p.i. and decreased significantly by 24 h p.i., with nearly complete washout by 48 h p.i. (c). Time–activity curves for whole body and organs that were easily discernible and metastatic sites generated from region of interest placed on whole-body scintigraphy images.
Figure 3
Figure 3
(a). [18F]F-Fluorodeoxyglucose (FDG) PET/CT images of a 50-year-old woman with follicular variant of papillary carcinoma, post radioiodine therapy (cumulative dose of 22.2 GBq) showing soft tissue density mass in left shoulder (arrows) and multiple skeletal lesions. (b). Whole body scintigraphy conducted after additional 7.4 GBq of radioiodine therapy, showing multiple foci of tracer accumulation suggestive of disease progression, who was started on Sorafenib (400 mg OD). (c). [68Ga]Ga- DOTA.SA.FAPi PET/CT images (performed after 6 months of Sorafenib therapy as part of ongoing clinical study when the patient had clinically progressive disease with thyroglobulin 300,000 ng/mL) show normal biodistribution in the oral mucosa, salivary glands, liver, pancreas, gall bladder, colon, and kidneys. Intense accumulation of radiotracer in the soft tissue mass (arrows) and multiple skeletal sites (right femur-arrow head). (d). Serial [177Lu]Lu-DOTAGA.(SA.FAPi)2 whole-body scintigraphy images for dosimetry, after intravenous injection of 1.48 GBq of radiotracer, showing radiotracer retention in the metastatic sites until 168 h delayed images. (e). Time–activity curves for whole body, organs that were easily discernible, and metastatic sites generated from region of interest placed on whole-body scintigraphy images. Accumulation in the normal organs peaked during 24–48 h and decreased significantly by 96 h post injection. Left shoulder, sternum, and right femur show persistent retention until 168 h delayed images. Patient received two cycles of [177Lu]Lu-DOTAGA.(SA.FAPi)2 therapy and showed significant clinical improvement with a decrease in thyroglobulin levels to 27,000 ng/mL. The patient also showed significant decrease in the VASmax score, from 10 to 5, in a follow-up at 4.5 months.
Figure 4
Figure 4
(a). A 27-year old male diagnosed with paraganglioma was treated with [177Lu]Lu-DOTAGA.(SA.FAPi)2 treatment, and the 1 h scan post-treatment showed (a) normal and minimal biodistribution of radiotracer in the oral mucosa, salivary glands, liver, pancreas, and kidneys. At 1 h p.i., intense accumulation of radiotracer was observed in the skull and rib lesions. The patient has a history of constipation and hence demonstrated persistent and intense uptake of [177Lu]Lu-DOTAGA.(SA.FAPi)2 radiotracer in the gut due to reduced intestinal motility, even at 168 h (b) post-treatment, reflecting higher radiation absorbed dose to the colon compared to the other patients, such the patient treated in Figure 3.
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