Personalized Radionuclide Therapy via Avidin-Biotin Pretargeting: Biodistribution and Dosimetry of 177 Lu-DOTA-biotin with AvidinOX™ in Solid Tumors

Abstract

Purpose:

AvidinOX^™ forms a long-lasting artificial receptor that supports effective in vivo binding of circulating biotinylated therapeutic ¹⁷⁷Lu-DOTA-biotin. We investigated the biodistribution and radiation dosimetry of ¹⁷⁷Lu-DOTA-biotin in patients with solid tumors following image-guided intratumoral AvidinOX administration.

Methods:

Three patients received intratumoral injections of AvidinOX and two cycles of intravenous administration of ¹⁷⁷Lu-DOTA-biotin over a period of 2 weeks. Multi-time-point whole-body planar and SPECT/CT imaging was performed post infusion. Blood and urine samples were collected over 7 days, and organ radiation doses were estimated using the Medical Internal Radiation Dose methodology.

Results:

Sequential imaging demonstrated favorable tumor-to-background ratios and sustained uptake of ¹⁷⁷Lu-DOTA-biotin within the pretargeted lesions, confirming effective localization and prolonged retention. Most of the administered activity was excreted via urine within 4 h post infusion. The absorbed tumor radiation dose ranged from 3.96 to 50.37 Gy, while bone marrow (0.15–0.22 Gy) and kidney (0.66–1.84 Gy) doses remained below established safety thresholds. There were no serious adverse events.

Conclusions:

Intratumoral AvidinOX achieved effective and durable localization of ¹⁷⁷Lu-DOTA-biotin without exceeding the maximum allowable radiation absorbed dose to critical organs. These first-in-human dosimetric data provide quantitative insight into tumor retention, off-target exposure, and therapeutic potential across solid tumors, supporting the rational design of future radionuclide therapy trials.

Keywords

solid tumors radionuclide therapy AvidinOX SPECT/CT radiation dosimetry

Introduction

Selective targeting cancerous tissues has posed a significant challenge in oncology for decades. Recent developments in radionuclide-based therapies have provided new opportunities for selective tumor irradiation. Classical brachytherapy represents one of the earliest approaches for delivering conformal radiotherapy directly to inoperable tumors through the placement of radioactive sources within or adjacent to the malignant tissues. It relies on a variety of complex medical devices such as needles, permanently implanted seeds, wires, or catheters to be placed directly into or near the targeted tumor.¹ Another manner to deliver targeted radiation to tumors is via systemic radioligand therapy (or simply radioligand therapy), in which a tumor-targeting therapeutic molecule delivers a radionuclide selectively to cancer cells. A best example is Pluvicto^® (¹⁷⁷Lu-PSMA-617), a radioligand therapy approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC).² The ligand component, PSMA-617, binds specifically to prostate-specific membrane antigen (PSMA) expressed in prostate tumor cells and provides targeted delivery of the ¹⁷⁷Lu, which induces DNA damage and subsequent tumor cell death with minimal off-target toxicity. Pluvicto was approved by the Food and Drug Administration for the treatment of adult patients with mCPRC in March 2022 based on the results of the VISION clinical trial, where Pluvicto was shown to significantly improve overall survival compared with standard therapy alone.³ Conceptually, both brachytherapy and radioligand therapy share the same therapeutic rationale, localized internal radiation delivery for maximal tumor therapeutic effect with minimal collateral normal tissue damage; however, they differ in their implementation: The brachytherapy approach achieves a spatial localization through physical implantation of radioactive devices, while radioligand therapy relies on preferential receptor-based uptake of the systemically distributed radiopharmaceuticals by the tumor.

The present study investigates a novel pretargeting method—designed to combine the spatial precision of local administration with the systemic selectivity of radioligand therapy. The approach is an evolution of Intraoperative Avidination for Radionuclide Therapy (IART) that was previously investigated for early breast cancer patients undergoing breast-conserving surgery with the intention to minimize the rate of local recurrence.^4,5 Traditionally, external beam radiation therapy (EBRT) is used after breast-conserving surgery to eradicate any microscopic residual disease and prevent local recurrence. Developed as an alternative to EBRT, IART involved intraoperative injection of avidin, along the surgical margins, followed by an intravenous injection of radioactive biotin 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (ST2210) within 24 h.⁶

Avidin is a glycoprotein obtained from hen egg white, and it is known to have the highest affinity for biotin (vitamin H).⁷ When avidin is administered directly into the tumor, it becomes an artificial receptor (creates a transient biotin receptor based on avidin’s tumor affinity) for intravenously administered biotin. This approach enables the use of biotinylated therapeutics, such as radionuclide-labeled biotin, which has been employed in several IART procedures.^4,6,8 However, despite these features, the pharmacokinetic profile of native avidin poses significant limitations. Preclinical studies have demonstrated that avidin exhibits rapid clearance from tissues, with less than 1% of the injected dose per 100 mg remaining at the injection site 24 h after intramuscular administration in mice.^9–11 Avidin diffuses from the injection site, with residual activity detected in liver and kidney.^9,10 To address these challenges, efforts have been made to prolong avidin’s tissue half-life and reduce off-target accumulation, through polyethylene glycol (PEG) conjugation (PEGylation), a strategy known to enhance the pharmacokinetics of protein-based therapeutics.^10,12 Furthermore, Avidin was oxidized with sodium periodate to obtain reactive aldehyde groups by a procedure designed to protect the biotin binding sites with a low-affinity ligand.^10,13 This avidin derivative, named AvidinOX^™, was shown to be able to form Schiff’s bases with tissue proteins following intratumor injection.^9,10 Preclinical data suggest that follow-up radionuclide administrations could be divided into multiple therapeutic cycles.¹⁴ AvidinOX is a long-lasting artificial receptor for circulating biotinylated therapeutics such as radioactive biotin ¹⁷⁷Lu-DOTA-biotin (also known as ¹⁷⁷Lu-ST2210).¹⁵ The mechanism by which AvidinOX achieves durable intratumoral retention is biochemically distinct from that of native avidin. AvidinOX is produced by 4-hydroxyazobenzene-2′-carboxylic acid-assisted avidin oxidation of the avidin glycoprotein, generating a reactive aldehyde group from the carbohydrate moieties, while preserving the biotin-binding sites from inactivation.^9,10 Upon intratumoral injection, these aldehydes react spontaneously at physiological pH with the ε-amino group of lysine residues on extracellular matrix and stromal protein, forming stable covalent Shiff’s bases that anchor AvidinOX within the tumor stroma for weeks (retaining in a tissue with a half-life of 2 weeks), compared with a tissue half-life of approximately 2 h for native avidin.^9,14,16

AvidinOX’s cationic charge further promotes preferential interaction with negatively charged extracellular matrix proteins, directing localization to tumor stroma, connective rim, and basal membrane of tumor-associated vessels.¹⁶ Such interaction allows the formation of Schiff’s bases. In fact, chemical modification of AvidinOX to lower its positive charge reverses its binding property. Once anchored, AvidinOX retains high-affinity biotin-binding capacity (Kd ∼10⁻¹⁵ M),⁷ functioning as a durable artificial receptor for intravenously administered ¹⁷⁷Lu-DOTA-biotin (¹⁷⁷Lu-ST2210).^9,15 Lutetium-177 (¹⁷⁷Lu) is an ideal nuclide for producing a therapeutic effect on neoplastic masses due to an emission of a 0.497 MeV β-particle, which travels approximately 670 μm. Additionally, the ¹⁷⁷Lu nuclide has a suitable physical half-life of 6.647 days and low-level photon emissions of 113 keV (yield 6.4%) and 208 keV (yield 11%). Thus, utilization of ¹⁷⁷Lu is advantageous due to its long half-life and dual beta and gamma emissions, which produce a therapeutic tumoral effect while also allowing for multiday scintigraphic imaging.^17,18

Research has shown that avidination can be a safe, effective, and simple approach for targeting radioactive biotin.⁸ In preclinical work by Vesci et al., intratumoral injection of AvidinOX followed by low-dose biotinylated cetuximab, with or without cisplatin, significantly reduced tumor growth in an orthotopic model while being well tolerated.¹⁹ The use of AvidinOX to enable targeted delivery of radioactive biotin to inoperable tumors was extensively investigated in preclinical models^9,14–16 and then explored in a clinical trial (NCT02053324). This study evaluated intratumoral injection of AvidinOX in the liver, followed by intravenous administration of ¹⁷⁷Lu-ST2210, with primary objectives focused on determining the maximum tolerated dose, assessing safety and tolerability, and characterizing biodistribution, pharmacokinetics, and tumor uptake of AvidinOX–¹⁷⁷Lu-ST2210 complex. Imaging-guided intratumoral injection of AvidinOX allows precise administration according to the size, shape, and location of the tumors. Because of the long residence time of AvidinOX in tumors for several days, it provides a prolonged window during which the appropriate therapeutic radionuclide can be administered and efficiently captured.

In the present study (NCT03188328), we explored the biodistribution and dosimetry of the novel radionuclide-based treatment and evaluated its therapeutic effects on tumors. This pilot study was designed as a dose escalation study to assess the safety, tolerability, pharmacokinetics, maximum tolerated dose, and preliminary efficacy of intratumoral injected AvidinOX (Fig. 1A), followed by systemic intravenous administration of escalating doses of ¹⁷⁷Lu-DOTA-biotin (Fig. 1B) in patients with solid tumors with resulting neoplastic lesions. This clinical trial required coordinated use of biological sampling, multi-point anterior and posterior whole-body planar and multi-point Single-Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) scintigraphic imaging to identify the biological distribution of the novel radiotracer, ¹⁷⁷Lu-DOTA-biotin. We estimated organ radiation absorbed doses by computing residence times based on serial gamma camera imaging. This was followed by calculation of absorbed dose estimates according to the methodology developed by the Medical Internal Radiation Dose (MIRD) Committee.²⁰ While NCT02053324 aimed at investigating maximum tolerated dose and safety in patients with hepatic colorectal metastases, it did not provide organ-specific or tumor-specific radiation dosimetry. The present study (NCT03188328) is, to the best of our knowledge, the first report of quantitative radiation dosimetry of this pretargeted system in patients with injectable solid tumors, providing the translational foundation required for rational design of future dose-escalation trials.

FIG. 1.

Molecular structure depictions of the AvidinOX^™ and the ¹⁷⁷Lu-DOTA-biotin. (A) AvidinOX-based targeting relies on the ability of avidin, a glycoprotein from hen egg white, to bind biotin (vitamin H) with very high affinity. Avidin has been chemically modified to obtain AvidinOX, which forms a chemical linkage with tissue proteins, thus leading to its permanence in tissues for weeks. (B) The ¹⁷⁷Lu-DOTA-biotin conjugate is designed for intravenous infusion 24 h post intratumoral AvidinOX administration.

Materials and Methods

The clinical trial (NCT03188328) was designed as a dose escalation trial with four planned dose intervals. The initial starting dose of ¹⁷⁷Lu-DOTA-biotin was 7.5 GBq ± 10%. Subsequent interval doses were increased by 2.5 GBq ± 10%, with a maximum planned dose level of 15 GBq ± 10%. These dosing cohorts were intended to identify the maximum tolerated dose that could be administered without exceeding the allowable radiation absorbed dose to critical organs.

AvidinOX and ¹⁷⁷Lu-DOTA-biotin

AvidinOX was administered intratumorally by an interventional radiologist using real-time ultrasound image guidance. The dosage of the AvidinOX (3 mg/mL) was prepared in an injectable volume equal to 15% of the estimated lesion volume, calculated as (0.15)4/3π (0.5d)³, where d represents the longest tumor diameter based on preprocedural imaging parameters. For treating multiple lesions, the maximum total injectable volume of AvidinOX was 75 mL combined across all targeted lesions per treatment session. This upper limit was derived from the prior trial (NCT02053324).

The ¹⁷⁷Lu-DOTA-biotin was administered as an intravenous infusion 24 h and 14 days post intratumoral AvidinOX administration. The radiopharmaceutical was supplied in a ready-to-use patient vial with a volume of 25 mL containing 1 mg ST2210 (DOTA-biotin complex) conjugated to 7.5 GBq ± 10% of ¹⁷⁷Lu. Therefore, the specific activity of ¹⁷⁷Lu-DOTA-biotin was 7.5 GBq/mg. ¹⁷⁷Lu-DOTA-biotin was intravenously infused over 30 min via a peristaltic pump. The starting dose of ¹⁷⁷Lu-DOTA-biotin was 7.5 GBq ± 10% with planned dose escalation steps of 2.5 GBq up to 15 GBq ± 10% per therapeutic cycle. AvidinOX was supplied by ARETA International s.r.l., via Roberto Lepetit 34, 21040 Gerenzano (VA), Italy; ¹⁷⁷Lu-ST2210 was supplied by Seibersdorf Laboratories, 2444 Seibersdorf, Austria.

Specimen collections

A series of blood and urine samples was collected to evaluate the biological clearance of the ¹⁷⁷Lu-DOTA-biotin. During each therapeutic administration, 15 blood samples were collected ranging from pretherapeutic infusion to 7 days post infusion. Blood samples were collected from the opposite extremity of the ¹⁷⁷Lu-DOTA-biotin administration site to avoid any residual radiopharmaceutical contamination of the blood samples. During the first cohort, all patients were required to be urinary catheterized for 48 h post infusion. Six urine samples were collected from pretherapeutic infusion to 48 h post infusion. The urinary catheter allowed for accurate collection of urine eliminating the need for the patient to collect and providing a urine specimen at various time points.

Approximately 4 mL of each blood and urine sample was assayed along with a ¹⁷⁷Lu counting standard, to derive radioactivity concentration versus time using a multichannel well counter (Perkin-Elmer Wizard, Waltham, MA). Data were expressed as a fraction of injected activity per mL.

Scintigraphic imaging

Prior to the therapeutic administration of ¹⁷⁷Lu-DOTA-biotin, each patient was custom fitted to a whole-body immobilization device. The patient immobilization device was utilized for all post infusion scintigraphic imaging, thus ensuring consistent and accurate patient positioning for all subsequent imaging procedures. Following the therapeutic administration of ¹⁷⁷Lu-DOTA-biotin, five whole-body planar images were acquired using a rate of 10 cm/min at 0.5 h, 6 h, 24 h, 72 h, and 11 days post infusion. In addition, five one-bed SPECT/CT images were acquired over the targeted lesion for 20 s per view and 128 views over 360° at 1 h, 6.5 h, 24.5 h, 72.5 h, and 7 or 11 days post infusion. Medium energy collimators were utilized, and the gamma energy window was centered on the 208 keV photopeak with a ±15% variance for both planar and SPECT acquisitions. Scintigraphic images were acquired using a dual-head Symbia T16 SPECT/CT (Siemens Medical Solutions, Erlangen, Germany).

Image analysis for dosimetry calculations

Three-dimensional volume-of-interests (VOIs) of identifiable source organs of radioactivity were manually defined on the first-day CT scan, and all serial SPECT scans were manually registered to that CT scan using MIM version 6.5 (MIM Software Inc., Beachwood, OH). The use of a patient immobilization device made transfer of VOIs across multiple time points more straightforward, ensuring consistent longitudinal dosimetry analysis. These VOIs were used for both CT-based organ mass estimation and SPECT organ activity versus time (time–activity curve [TAC]) generation. Two-dimensional total body regions of interest were defined in an analogous fashion using the planar whole-body scan images for total-body TAC generation. Radiation absorbed dose was calculated for vital organs and the targeted lesion for each ¹⁷⁷Lu-DOTA-biotin treatment cycle. The liver was not included as an organ of interest for dosimetric analysis, as hepatic uptake of ¹⁷⁷Lu-DOTA-biotin was below the threshold for reliable volumetric contouring in all three patients, consistent with the known absence of nonspecific hepatic sequestration in AvidinOX-pretargeted radionuclide therapy.⁹

Exposure measurements

After each administration of the radiotherapeutic component, patient exposure was recorded at 1 m utilizing a digital calibrated exposure-rate meter. Serial exposure-rate measurements were collected post administration and repeated on days of scintigraphic imaging. Each patient was carefully surveyed for the highest radiation exposure measurement utilizing the digital exposure-rate meter. Radiation exposure data were also used to monitor patients for safety and compliance with radiation protection guidelines. Exposure measurements were intended to investigate post infusion patient radiation release considerations and whether the therapeutic amount of radiotracer warranted inpatient treatment.

Patients

For this initial cohort, three patients participated in this clinical trial. All patients presented with inoperable lesion(s) from histologically confirmed solid tumors with at least one lesion measuring ≥1 cm and suitable for intralesional injection. Additionally, all patients displayed disease progression with available therapeutics. These patients had varying histologies of injectable tumors: Patient 1, a 62-year-old female with a history of dedifferentiated liposarcoma of the abdomen (Fig. 2, ¹⁸F-FDG positron emission tomography/computed tomography [PET/CT] image). This clinical trial participant had previously received multiple lines of systemic therapy, but the sarcoma continued to progress. Patient 2, a 62-year-old female with a history of histiocytoma of the right thigh; Patient 3, a 58-year-old male with a history of adenocarcinoma of the sigmoid colon with peritoneal metastasis (Table 1). All patients agreed and consented to participate in the clinical trial.

FIG. 2.

A 62-year-old woman (Patient 1) with dedifferentiated liposarcoma involving the musculature of the lower anterior abdominal wall. (A) Axial ¹⁸FDG PET/CT, (B) CT, and (C) PET images demonstrate increased radiotracer uptake in portions of a 7.4 × 6.8 cm soft tissue mass (SUV_max = 15.0, arrows). Coronal (D), sagittal (E), and PET/CT and Maximum Intensity Projection image (F) of the same patient. PET/CT, positron emission tomography/computed tomography.

Table 1.

Patient Demographics and ¹⁷⁷Lu-DOTA-biotin Treatment Characteristics

Characteristics	Patient 1	Patient 2	Patient 3
Age (years)	62	62	58
Gender	Female	Female	Male
Targeted tumors	Dedifferentiated liposarcoma	Histiocytoma	Sigmoid colon adenocarcinoma
Body region	Abdomen	Right thigh	Adenocarcinoma with metastatic disease
Administered activity per cycle, GBq	7.5 ± 10%	7.5 ± 10%	7.5 ± 10%
Number of treatment cycles	2	2	2

These three patients were administered AvidinOX intratumorally followed by two intravenous therapeutic cycles of ¹⁷⁷Lu-DOTA-biotin each in a volume up to 25 mL consisting of 1 mg ST2210 (DOTA-biotin complex) conjugated to 7.5 GBq ± 10% of ¹⁷⁷Lu-DOTA-biotin. Figure 3 is a representative schema of the two-step pretargeting radionuclide therapy protocol in this clinical trial.

FIG. 3.

Schematic overview of the two-step pretargeting radionuclide therapy protocol. Following screening and lesion localization, patients underwent imaging-guided intratumoral injection of AvidinOX^™ (3 mg/mL, volume equal to 15% of estimated tumor volume) on Day 0, administered by interventional radiology under real-time ultrasound or CT guidance. Cycle 1 of ¹⁷⁷Lu-DOTA-biotin (7.5 GBq ± 10%/1 mg ST2210) was administered as a 30-min intravenous infusion on Day 1, followed by dosimetry data collection consisting of serial urine and blood sampling and multi-time-point SPECT/CT imaging. Cycle 2 of ¹⁷⁷Lu-DOTA-biotin was administered on Day 15, with a repeated dosimetry protocol extending through Day 22.

Results

Per protocol, the patient’s temperature, pulse rate, and oxygen saturation levels were routinely monitored, as well as electrocardiographic parameters and laboratory results. Patients did not exhibit any significant variation in health status with respect to baseline conditions. All patients tolerated the AvidinOX and therapeutic cycles of ¹⁷⁷Lu-DOTA-biotin well with no display of adverse reactions.

Exposure measurements

Patient release criteria were evaluated using the administered activities, measured exposure rates, and patient-specific effective half-life. The net administered activity for the cohort ranged from 7.36 to 7.57 GBq. The calculated effective half-life from the first and second intravenous therapeutic cycles of ¹⁷⁷Lu-DOTA-biotin administration was 2.51–2.68 h and 5.42–6.72 h, respectively. For example, the patient identified in Figure 2, who had a neoplastic lesion selected for treatment, received 18.7 mL of AvidinOX, administered directly into the abdominal tumor via real-time ultrasound image guidance. Immediately following the ¹⁷⁷Lu-DOTA-biotin infusion, the highest recorded exposure rate at 1 m was 1.07 mR/h. After the required in-patient hospital stay per protocol, the exposure rate, associated with an administered activity of approximately 7.5 GBq and measured effective half-life (<7 h), was used for patient release (public dose <100 mrem) with minimal radiation safety instructions under federal code 10 of the Code of Federal Regulations 35 (10 CFR 35) and the associated guidance in NUREG-1556.²¹

Post AvidinOX and ¹⁷⁷Lu-DOTA-biotin SPECT biodistribution

Multi-time-point planar scintigraphic and SPECT/CT acquisitions that aid in the visualization of radiopharmaceutical indicated excellent in vivo binding of the AvidinOX to ¹⁷⁷Lu-DOTA-biotin within the targeted neoplastic lesion. Twenty-four hours post AvidinOX, the patient received 7.5 GBq ± 10% of ¹⁷⁷Lu-DOTA-biotin intravenously over a 30-min period. Figure 4 shows the sequential anterior planar images from 0.5 h through 11 days post ¹⁷⁷Lu-DOTA-biotin administration. The anterior 0.5-h planar image demonstrates rapid radiotracer blood pool and renal clearance. The 24-h anterior planar image demonstrates minimal blood pool distribution; mild uptake in the liver, spleen, and bone marrow; and better visualization of the targeted abdominal lesion. The 11 days post ¹⁷⁷Lu-DOTA-biotin confirms the long-lasting enhanced tumor binding.

FIG. 4.

Anterior planar images were acquired 0.5 h through 11 days following administration of ¹⁷⁷Lu-DOTA-biotin. The solid black arrow arow identifies the targeted abdominal lesion. The white asterisk indicates the urinary bladder. The data demonstrates intense radiotracer uptake in the pretargeted lesion consistently from 1-h through 11 days post infusion per each therapeutic cycle. The investigational radiopharmaceutical shows effective tumor localization on scintigraphic imaging.

The localization of ¹⁷⁷Lu-DOTA-biotin to AvidinOX is better appreciated in the fused axial abdominal SPECT/CT acquisitions for both treatment cycles, as depicted in Figures 5 and 6. The first image in Figure 5, acquired 1 h post ¹⁷⁷Lu-DOTA-biotin administration, demonstrated mild radiotracer uptake within the tumor. Additional cycle-one axial SPECT/CT images acquired 24 h through 11 days post administration demonstrate heterogeneous increased radiopharmaceutical uptake within the pretargeted soft tissue sarcoma, further suggesting acceptable targeting and confirming acceptable distribution and retention of the AvidinOX to ¹⁷⁷Lu-DOTA-biotin. Images of additional patients are depicted in Figures 6–8.

FIG. 5.

Cycle 1 and Cycle 2 SPECT/CT acquisitions. The pretargeted abdominal wall mass injected with AvidinOX™ under ultrasound guidance. Subsequently, ¹⁷⁷Lu-DOTA-biotin was administered intravenously for two therapeutic cycles, followed by multitime point axial SPECT/CT imaging (patient 1).

FIG. 6.

SPECT/CT images obtained at 72 h after the intravenous administration of ¹⁷⁷Lu-DOTA-biotin. Two weeks prior to radiotracer injection, 6.9 mL of oxidized avidin was administered intratumorally under ultrasound guidance by interventional radiology. Axial SPECT/CT (A), CT (B), SPECT (C), coronal (D), sagittal SPECT/CT (E), and coronal SPECT (F) images of Patient 1.

FIG. 7.

Fused SPECT/CT images of a 62-year-old female (Patient 2) with malignant fibrous histiocytoma after administration of ¹⁷⁷Lu-DOTA-biotin. Intense radiotracer activity is noted in the right mid-thigh medially. Axial SPECT/CT (A), CT (B), SPECT (C), coronal (D) and sagittal (E) SPECT/CT, and coronal SPECT (F) images of Patient 2.

FIG. 8.

SPECT, CT, and fused SPECT/CT series of axial, sagittal, and coronal images of a 58-year-old male (Patient 3) with adenocarcinoma of the sigmoid colon after administration of ¹⁷⁷Lu-DOTA-biotin. Intense radiotracer uptake is identified within the midline pelvis anteriorly at the site of a known metastasis.

Dosimetry

Bone marrow absorbed dose is one of the limiting factors when administering radiopharmaceutical treatments. The ¹⁷⁷Lu-DOTA-biotin dose level in this study indicates a low radiation exposure to bone marrow. At the 7.5 GBq level, the highest bone marrow absorbed dose was calculated to be 0.216 Gy (ranging from 0.152 to 0.216 Gy), and this is well below the 2 Gy threshold.^22,23

The TACs revealed rapid radiopharmaceutical radiotracer exponential clearance with most of the radiopharmaceutical cleared via the kidneys in the first 8–12 h post ¹⁷⁷Lu-DOTA-biotin administration. These TACs for tumors and organs could be characterized using monoexponential functions, reflecting the primary clarence kinetics of the radiopharmaceutical.

The urine clearance rate was (T_1/2) was calculated to be 1.1–3.2 h for the first dosing injection and 2.2–2.7 h for the second dosing injection, reflecting the rapid renal elimination half-life (Table 2). Blood and urine sample were collected at multiple time points during each therapeutic cycle. Samples were stored and measured at the end of all imaging sessions in a single counting session using a multichannel well counter. Appropriate dilutions were made to avoid deadtime losses during counting, and all measurements were corrected for decay and dilutions to determine the true activity of each sample. Post infusion scintigraphic images (Fig. 4) indicate ¹⁷⁷Lu-DOTA-biotin is rapidly excreted via the kidneys. The highest total renal absorbed dose was calculated to be 1.838 Gy (ranging from 0.664 to 1.838 Gy), which is significantly below the critical organ threshold of 23 Gy for the kidney.²³

Table 2.

Estimated Doses from the Two Doses of 7.5 GBq of ¹⁷⁷Lu-DOTA-biotin

Source organ	Normalized absorbed dose (mGy/MBq)	Total dose (Gy)	Extrapolated total dose (Gy)
Whole body	0.017–0.029	0.132–0.217	2.4
Red marrow	0.020–0.029	0.152–0.216	2.4
Kidney	0.089–0.239	0.664–1.838	20.2
Tumor	0.519–6.743	3.964–50.369	40–500
Urine clearence	Rate of clearance T_1/2 (h)	Net urine extracted per administered activity
First treatment	1.1–3.2	0.98–1.05
Second treatment	2.2–2.7	1.01–1.02

The estimated total absorbed radiation dose to tumors ranged from 3.96 to 50.37 Gy after two therapeutic cycles of ¹⁷⁷Lu-DOTA-biotin 7.5 GBq ± 10%, administered 14 days apart.

The normalized absorbed doses to the organs and tumors were summarized in Table 2. The dosimetry calculations for 7.5 GBq dose were extrapolated for 11 treatment cycles to estimate the total absorbed dose for an 82.5 GBq (11 × 7.5 GBq) administration, demonstrating that this would approach the safety limit for kidney absorbed dose of 23 Gy.

Discussion

All patients tolerated AvidinOX and ¹⁷⁷Lu-DOTA-biotin well with no adverse reactions reported. According to the dosimetry data, patients may be able to receive much higher doses of ¹⁷⁷Lu-DOTA-biotin without exceeding safety limits for critical organs. This is likely due to the rapid radiopharmaceutical clearance from all major organs, while retaining a high radiation dose to tumors, estimated at up to 50.37 Gy at the 7.5 GBq dose level. Sequential SPECT/CT acquisitions confirmed persistent and heterogeneous intratumoral uptake of ¹⁷⁷Lu-DOTA-biotin up to 11 days post administration, supporting the prolonged tumor retention inferred from dosimetry data. In the present study, the absorbed doses to bone marrow and kidneys remain largely below clinically established safety thresholds. Overall, the 7.5 GBq dose level demonstrates minimal radiation exposure to bone marrow and kidneys, providing support for further dose-escalating studies.

When extrapolated to an accumulated dose of 82.5 GBq over 11 treatment cycles, the projected tumor absorbed dose could reach approximately 500 Gy. We hypothesize that such a tumor-targeted accumulated dose may result in favorable dose–response relationship. This is consistent with previously published reports, where a significant correlation was observed between absorbed dose and tumor reduction using ¹⁷⁷Lu-DOTATATE, where tumor-absorbed doses associated with the best response ranged approximately from 10 to 340 Gy.²⁴

This therapeutic approach introduces a hybrid concept that merges the spatial precision of brachytherapy with the molecular selectivity of radioligand therapy, creating a new platform for targeted endo-radiotherapy. The cornerstone of this clinical trial is based on the strong biochemical attraction of ¹⁷⁷Lu-DOTA-biotin to AvidinOX. In fact, the direct intratumoral injection of AvidinOX followed by the intravenous administration of ¹⁷⁷Lu-DOTA-biotin results in a strong and stable in vivo complex with a long tissue residence time.^9,16,25,26

The two-step pretargeting strategy offers critical advantages over direct intratumoral injection of a radiolabeled avidin derivative. When administered intravenously, AvidinOX distributes substantially to the liver, spleen, and kidney, as was demonstrated in preclinical pharmacokinetic studies,¹⁵ thus making direct radiolabeling impractical due to unacceptable organ radiation exposure. By contrast, ¹⁷⁷Lu-DOTA-biotin is a small molecule that clears rapidly via renal excretion when unbound. This pattern was confirmed in the present study, where most of the administered activity was eliminated within 4 h of infusion, thereby minimizing systemic exposure of nontarget organs. Decoupling AvidinOX localization from radiolabeled delivery additionally allows independent dose escalation across treatment cycles and permits imaging confirmation of tumor uptake prior to each radioligand administration.

The intratumoral retention of AvidinOX is volume dependent and has been characterized in preclinical studies. Injection of an AvidinOX solution equal to 15% of the tumor volume was found sufficient to capture the intended therapeutic dose of ¹⁷⁷Lu-DOTA-biotin.^10,14 Consistent with this, data from NCT02053324 demonstrated a positive correlation between the percent of tumor volume injected and the resulting absorbed dose. In our study, the protocol was chosen to inject AvidinOX at 15% of the lesion volume.

The specific property of AvidinOX is that it chemically binds to tumor tissues after intratumoral administration while maintaining the capacity to take up circulating ¹⁷⁷Lu-DOTA-biotin. Once locally bound in neoplastic tissue, AvidinOX becomes an “artificial receptor” for intravenously injected ¹⁷⁷Lu-DOTA-biotin, which, in effect, results in internal radiation therapy of the tumor. The treatment of tumors with local injection of AvidinOX and the following intravenous injection of ¹⁷⁷Lu-DOTA-biotin may be simpler and more tolerable than the current available treatments. A unique advantage of direct intratumoral injection of AvidinOX is that it allows for precise radiotherapeutic administration. This mode of administration does not require a cell surface membrane for radiopharmaceutical localization. In several case studies, AvidinOX has reliably formed Schiff’s bases when directly administered in tissues.^{9,10,14,15,27} In this clinical trial, a single administration of AvidinOX displayed a long tumor residence, thereby allowing for multicycle radionuclide treatments. These distinctive characteristics can be exploited for patients who may not have benefited from previous systemic therapies.

Unresectable tumors are challenging to treat locally. Currently, external beam radiation or various forms of brachytherapy are used for such tumors. The combination of AvidinOX and ¹⁷⁷Lu-DOTA-biotin offers several advantages for targeted radionuclide therapy for inoperable cancer lesions. When AvidinOX is administered directly into a target tissue, the therapy can be tailored to the size, shape, and location of the tumor or organ, allowing for personalized and localized treatment. The stable tissue localization of AvidinOX to tissue proteins allows the uptake and in vivo binding of the ¹⁷⁷Lu-DOTA-biotin and avoids the complications associated with seed migration observed in brachytherapy. Direct lesion injections enable adequate diffusion of AvidinOX within the targeted area, improving therapeutic precision. Based on preclinical and clinical studies, including patients with liver metastases, it is reasonable to assume that intralesional administration of AvidinOX followed by intravenous delivery of ¹⁷⁷Lu-DOTA-biotin may represent a safe and effective treatment strategy for inoperable tumors.^6,14,15,19 As such, AvidinOX and ¹⁷⁷Lu-DOTA-biotin offer radiotherapeutic options to patients with histologically confirmed inoperable solid tumors. This pretargeted endo-radiotherapy is intended to distribute a high radiation-absorbed dose selectively to the target tumor tissue while minimizing exposure to surrounding normal organs.

In this study, the initial amount of ¹⁷⁷Lu-DOTA-biotin was guided by prior data from the European clinical trial, AvOX/ST2210-CR-12-001 (NCT02053324). In general, accurate whole-body and organ dosimetry critically depends on consistent patient positioning during both planar and SPECT/CT acquisitions. All patients tolerated the imaging procedures and intravenous infusion of ¹⁷⁷Lu-DOTA-biotin well, with minimal discomfort due to the immobilizer. The use of the immobilizer was instrumental in achieving fusion alignment of planar and SPECT/CT images, thereby decreasing the possibility of significant errors due to organ volume contouring or dose calculation errors from image misregistration. The presented scintigraphic images demonstrate consistent blood pooling and rapid renal clearance of the radiopharmaceutical, reinforcing the strong and specific locations of ¹⁷⁷Lu-DOTA-biotin to AvidinOX, as seen in Figure 2.

Although renal excretion is the primary elimination pathway for ¹⁷⁷Lu-DOTA-biotin, several patient-related factors, such as age, prior chemotherapy, and comorbidities including diabetes and hypertension,^23,28,29 might affect renal function and consequently influence the radiation dose absorbed by the kidneys. Therefore, one of the aims of this study was to evaluate the feasibility of administering a therapeutic dose while ensuring that the absorbed dose to the kidneys did not exceed 23 Gy. New emerging data from therapies such as ¹⁷⁷Lu-DOTATATE (Lutathera^®) suggest that the dosimetric thresholds for organs may be conservative. For example, a recent report by Bodei et al.³⁰ reported that patients who received absorbed renal doses ranging from 28 to 33 Gy experienced no severe renal toxicity, with follow-up extending up to 5 years. In the same study, one patient from the same study received 3 Gy in the bone marrow and experienced grade 3 lymphopenia, which resolved over time and did not progress to more severe hematological toxicity.³⁰ Bergsma et al. found that selected patients who received additional cycles of ¹⁷⁷Lu-DOTATATE had a mean bone marrow dose up to 3 Gy, with only limited hematological side-effects.³¹ Supporting this, Hebert et al. reported total absorbed bone marrow doses of up to 3.74 Gy in patients with gastroenteropancreatic neuroendocrine tumors, again with manageable toxicity profiles.³² Furthermore, historical data in thyroid cancer patients treated with ¹³¹I also align with a similar threshold. Dorn et al. proposed a bone marrow dose limit of 3 Gy based on an analysis of 83 patients.³³ Our data suggest that even when extrapolated to an accumulated dose to bone marrow of 2.4 GBq over 11 treatment cycles, exceeding the historically conservative 2 Gy limit, the overall safety profile would remain acceptable. This aligns with the above findings, supporting the potential of personalized dosimetry to tailor treatment doses for optimal tumor targeting and improved disease control.

Based on these dosimetric findings, and in line with emerging clinical data, we propose that up to 11 doses of ¹⁷⁷Lu-DOTA-biotin might be administered without inducing significant nephrotoxicity or unacceptable hematological toxicity. This further reinforces the rationale for reevaluating current standard dosimetric thresholds for renal and bone marrow exposure.^30,34

Limitation and future direction

As a Phase I dose-escalation study, this trial was designed to characterize safety, pharmacokinetics, and radiation dosimetry. Formal efficacy assessment was not an endpoint, and it will be addressed in further Phase II investigation. This pilot study involved a small number of patients, limiting statistical analysis of efficacy. Nevertheless, heterogeneous tumor types and lesion locations confirmed AvidinOX linkage and biotin uptake. Potential variability in AvidinOX retention due to lesion morphology or operator manuality is mitigated by the covalent Schiff’s base anchoring mechanisms, which govern intratumoral retention through chemical reactivity rather than passive diffusion.^9,16 The ¹⁷⁷Lu-DOTA-biotin uptake observed on multi-time-point SPECT/CT across all three patients, representing different tumor types and anatomical locations, supports effective and reproducible AvidinOX function independently of tumor morphology.

Future studies should evaluate escalation dose regimens, assess tumor response quantitatively, and correlate absorbed dose with clinical outcomes such as metabolic response and progression-free survival.

Conclusion

The combination of radiological image-guided injection of AvidinOX followed by intravenous administration of ¹⁷⁷Lu-DOTA-biotin at a dose of 7.5 GBq was well tolerated without serious adverse events in all three patients. To our knowledge, this represents the first dosimetric characterization of the AvidinOX + ¹⁷⁷Lu-DOTA-biotin pretargeting system in patients with solid tumors. Based on the dosimetry data collected from this cohort of patients, it can be concluded that the administered AvidinOX could be a receptor for much higher doses of ¹⁷⁷Lu-DOTA-biotin without exceeding the maximum allowable threshold for the bone marrow or kidneys, while achieving high tumor radiation-absorbed doses. Further investigation with escalating dose amounts is needed to identify the maximum tolerated dose for ¹⁷⁷Lu-DOTA-biotin for patients with solid tumors with injectable neoplastic lesions. Future trials should also explore correlations between absorbed dose and clinical outcomes to establish predictive dosimetry models. A major advantage of the intratumoral delivery of AvidinOX subsequent intravenous delivery of ¹⁷⁷Lu-DOTA-biotin combination is its adaptability to variable tumor geometry, supporting the concept of truly personalized radionuclide therapy.

Authors’ Contributions

F.G.: Conceptualization, methodology, data curation, writing—original draft preparation, and investigation. V.S.: Conceptualization, methodology, and data curation. S.C.K.: Methodology, data curation, and writing—reviewing and editing. L.M.: Visualization and writing—reviewing and editing. G.S.: Data curation and investigation. R.M. and R.D.S.: Conceptualization, methodology, and writing—reviewing and editing. G.R.: Conceptualization, methodology, investigation, and writing—reviewing and editing.

Footnotes

Ethics Approval and Informed Consent

Protocol approval of the study was obtained from the institutional investigational review board under the number 2016–0262. Informed consent was obtained from all individuals who participated in this clinical trial.

Disclosure Statement

F.G. reports a grant from FUJIFILM Pharmaceuticals U.S.A. during the conduct of the study. He was employed by MD Anderson Cancer Center at the time this clinical trial was conducted and is currently employed by Novartis Pharmaceuticals Corporation. Novartis had no involvement in the study, including, but not limited to, its design, funding, execution, data analysis, or article preparation. S.C.K. reports grants from Boston Scientific, Sirtex Medical, and ABK Biomedical, as well as consultantship with Boston Scientific, Sirtex Medical, and ABK Biomedical during the conduct of the study. G.R. reports grants from FUJIFILM Pharmaceuticals U.S.A., Inc., during the conduct of the study, as well as grants from Blue Earth Diagnostics, Inc. (U.S.A.), ABX GmbH, Alfasigma S.p.A., Novartis, Bayer, Amgen, Regeneron Pharmaceuticals Inc, Curium, and Clarity outside the submitted work. V.S. reports grants from FUJIFILM Pharmaceuticals U.S.A., Inc., (clinical trials research support) during the conduct of the study; additional grants from FUJIFILM Pharmaceuticals U.S.A. outside the submitted work; research funding/grant support for clinical trials from Roche/Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Northwest Biotherapeutics, Berghealth, Incyte, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfasigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology, Medimmune, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP, UT MD Anderson Cancer Center, Turning Point Therapeutics, and Boston Pharmaceuticals; travel support from Novartis, Pharmamar, ASCO, ESMO, Helsinn, and Incyte; consultancy/advisory board relationships with Helsinn, Loxo Oncology/Eli Lilly, R-Pharma US, Incyte, QED Pharma, Medimmune, Novartis, and Signant Health; and other relationships with Medscape.

Funding Information

This study was funded in part by Alfasigma S.p.A.

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Personalized Radionuclide Therapy via Avidin-Biotin Pretargeting: Biodistribution and Dosimetry of 177 Lu-DOTA-biotin with AvidinOX™ in Solid Tumors

Abstract

Purpose:

Methods:

Results:

Conclusions:

Keywords

Introduction

Materials and Methods

AvidinOX and 177Lu-DOTA-biotin

Specimen collections

Scintigraphic imaging

Image analysis for dosimetry calculations

Exposure measurements

Patients

Results

Exposure measurements

Post AvidinOX and 177Lu-DOTA-biotin SPECT biodistribution

Dosimetry

Discussion

Limitation and future direction

Conclusion

Authors’ Contributions

Footnotes

Ethics Approval and Informed Consent

Disclosure Statement

Funding Information

References

AvidinOX and ¹⁷⁷Lu-DOTA-biotin

Post AvidinOX and ¹⁷⁷Lu-DOTA-biotin SPECT biodistribution