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,Madhav Prasad Yadav,Euy Sung Moon,Vasko Kramer,Frank Roesch,Samta Kumari,Chandrasekhar Bal +6 more
TLDR
In this article, the authors evaluated and compared the biodistribution, pharmacokinetics, and dosimetry of [177Lu]Lu-DOTA.SA.FAPi2 in patients with various cancers.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.read more
Citations
More filters
Journal ArticleDOI
A Dimeric FAP-Targeting Small-Molecule Radioconjugate with High and Prolonged Tumor Uptake
Andrea Galbiati,Aureliano Zana,Matilde Bocci,Jacopo Millul,Abdullah Elsayed,Jacqueline Mock,Dario Neri,Samuele Cazzamalli +7 more
TL;DR: 177Lu-BiOncoFAP is a promising candidate for radioligand therapy of cancer, with favorable in vivo tumour-to-organ ratio, long tumour residence time and potent anti-cancer efficacy.
Journal ArticleDOI
Development of Fibroblast Activation Protein Inhibitor-Based Dimeric Radiotracers with Improved Tumor Retention and Antitumor Efficacy.
Qiang Zhao,Jianhao Chen,Yizhen Pang,Jianyang Fang,Kaili Fu,Lingxin Meng,Xian-Zheng Zhang,Zhide Guo,Hua Wu,Long Sun,Guoqiang Su,Qin Lin,Haojun Chen +12 more
TL;DR: DOTA-2P(FAPI)2 has increased tumor uptake and retention properties compared to FAPI-46, which significantly improves the use of FAP-based vectors for PET imaging and radionuclide therapy.
Journal ArticleDOI
FAPI PET: Fibroblast Activation Protein Inhibitor Use in Oncologic and Nononcologic Disease.
Yuriko Mori,Katharina Dendl,Jens Cardinale,Clemens Kratochwil,Frederik L. Giesel,Uwe Haberkorn +5 more
TL;DR: In this paper , a review of the state of the art in FAP imaging, summarizes the current knowledge of relevant cancer biology, and highlights the latest findings in the clinical use of 68Ga-FAPI PET and other current FAPI tracers.
Journal ArticleDOI
Production of GMP-Compliant Clinical Amounts of Copper-61 Radiopharmaceuticals from Liquid Targets
Alexandra Fonseca,Vitor Alves,Sergio J. C. do Carmo,Magda Silva,Ivanna Hrynchak,Francisco Alves,Amílcar Falcão,Antero J. Abrunhosa +7 more
TL;DR: It is demonstrated, for the first time, that clinical doses of 61Cu-based radiopharmaceuticals can easily be obtained in centres with a typical biomedical cyclotron optimised to produce 18F-based Radionuclidic purity.
Journal ArticleDOI
Associations between Normal Organs and Tumor Burden in Patients Imaged with Fibroblast Activation Protein Inhibitor-Directed Positron Emission Tomography
Aleksander Kosmala,Sebastian Serfling,N. Dreher,Thomas Lindner,Andreas Schirbel,Constantin Lapa,Takahiro Higuchi,Andreas K. Buck,Alexander Weich,Rudolf A. Werner +9 more
TL;DR:
References
More filters
Journal ArticleDOI
Tolerance of normal tissue to therapeutic irradiation.
B. Emami,John Lyman,A.P. Brown,Lawrence R. Coia,Michael Goitein,John E. Munzenrider,Brenda Shank,Lawrence J. Solin,Michael F. Wesson +8 more
TL;DR: The updated information on tolerance of normal tissues of concern in the protocols of this contract, based on available data, is presented, with a special emphasis on partial volume effects.
Journal Article
MIRDOSE: Personal Computer Software for Internal Dose Assessment in Nuclear Medicine
Journal ArticleDOI
Development of Quinoline-Based Theranostic Ligands for the Targeting of Fibroblast Activation Protein
Thomas Lindner,Anastasia Loktev,Anastasia Loktev,Anastasia Loktev,Annette Altmann,Annette Altmann,Frederik L. Giesel,Clemens Kratochwil,Jürgen Debus,Jürgen Debus,Dirk Jäger,Walter Mier,Uwe Haberkorn +12 more
TL;DR: FAPI-04 represents a promising tracer for both diagnostic imaging and, possibly, targeted therapy of malignant tumors with a high content of activated fibroblasts, such as breast cancer.
Journal ArticleDOI
Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: the role of associated risk factors.
Lisa Bodei,Marta Cremonesi,Mahila Ferrari,Monica Pacifici,Chiara Maria Grana,Mirco Bartolomei,Silvia M. Baio,Maddalena Sansovini,Maddalena Sansovini,Giovanni Paganelli +9 more
TL;DR: The results indicate the importance of clinical screening for risk factors and Fractionation of therapy is important in order to decrease toxicity, and further studies are needed to evaluate its clinical impact.
Journal Article
Bone marrow dosimetry for radioimmunotherapy: theoretical considerations.
TL;DR: A simple equation is presented which may be used to calculate the red marrow-to-blood activity concentration ratio given the hematocrit and thered marrow extracellular fluid fraction of a patient.