First-in-Human Safety, Imaging, and Dosimetry of a Carbonic Anhydrase IX–Targeting Peptide, [68Ga]Ga-DPI-4452, in Patients with Clear Cell Renal Cell Carcinoma

Visual Abstract [68Ga]Ga-DPI-4452, a first-in-class carbonic anhydrase IX–binding radiolabeled peptide, is the imaging agent of a theranostic pair with [177Lu]Lu-DPI-4452, developed for selecting and treating patients with carbonic anhydrase IX–expressing tumors. Here, [68Ga]Ga-DPI-4452 imaging characteristics, dosimetry, pharmacokinetics, and safety were assessed in 3 patients with clear cell renal cell carcinoma. Methods: After [68Ga]Ga-DPI-4452 administration, patients underwent serial full-body PET/CT imaging. Blood and urine were sampled. Safety was monitored for 7 d after injection. Results: Tumor uptake was observed at all time points (15 min to 4 h). Across 36 lesions, the SUVmax at 1 h after administration ranged from 6.8 to 211.6 (mean, 64.6 [SD, 54.8]). The kidneys, liver, and bone marrow demonstrated low activity. [68Ga]Ga-DPI-4452 was rapidly eliminated from blood and urine. No clinically significant toxicity was observed. Conclusion: [68Ga]Ga-DPI-4452 showed exceptional tumor uptake in patients with clear cell renal cell carcinoma, with very high tumor-to-background ratios and no significant adverse events, suggesting potential diagnostic and patient selection applications.

The CAIX-binding cyclic peptide DPI-4452, labeled with diagnostic ( 68 Ga) or therapeutic ( 177 Lu) radioisotopes, provides a novel theranostic pair to target CAIX-expressing tumors.Here, we report the characteristics of diagnostic [ 68 Ga]Ga-DPI-4452 in patients with ccRCC.

Patient Population and Study Design
This first-in-human, open-label, nonrandomized, multicenter phase 1/2 study (NCT05706129) aims to assess the safety, tolerability, and imaging characteristics of [ 68 Ga]Ga-DPI-4452 (part A) and the safety, efficacy, and therapeutic potential of [ 177 Lu]Lu-DPI-4452 (parts B and C) in patients with unresectable locally advanced or metastatic solid tumors (Supplemental Fig. 1; supplemental materials are available at http://jnm.snmjournals.org)(13,14).
Results from the completed ccRCC imaging cohort (part A) are reported.Patients with histologically confirmed unresectable, locally advanced or metastatic ccRCC must have received at least 2 lines of treatment in the metastatic setting (including a tyrosine kinase inhibitor and an immune checkpoint inhibitor).Further inclusion and exclusion criteria are in the supplemental methods.The primary objective of part A was to evaluate the safety and tolerability of a single intravenous injection of [ 68 Ga]Ga-DPI-4452.Secondary objectives included establishment of optimal imaging procedures for positive lesions, biodistribution assessment, dosimetry, pharmacokinetics, and concordance between [ 68 Ga]Ga-DPI-4452 PET imaging and conventional imaging.The study was institutional review board-approved, and patients provided written informed consent.

Imaging and Dosimetry
Patients underwent whole-body PET/CT at 15 min, 1 h, 2 h, and 4 h after [ 68 Ga]Ga-DPI-4452 administration.Determination of tumor lesions was based on SUV max and SUV mean .Regions of interest were drawn on PET/CT images over critical organs and tumor lesions to generate time-activity curves, calculate tumor-to-background ratios per time point, and assess radioactivity residence times.Dosimetry assessments were based on timeactivity curves and time-integrated activity coefficients to determine effective dose and absorbed dose per organ (supplemental methods).

Pharmacokinetics
Blood and urine were collected before, and at time points up to 6 h after, [ 68 Ga]Ga-DPI-4452 dosing and were analyzed onsite with a calibrated g-counter.

Safety Assessment
Safety and tolerability were assessed up to 7 d after [ 68 Ga]Ga-DPI-4452 administration (supplemental methods).

RESULTS
Three patients with metastatic ccRCC, aged 48, 51, and 54 y, were enrolled in a single center.All patients had an Eastern Cooperative Oncology Group performance status of 1 or less and had received at least 2 prior lines of systemic therapy (Supplemental Table 1).The mean administered [ 68 Ga]Ga-DPI-4452 activities were 174, 198, and 198 MBq.
After [ 68 Ga]Ga-DPI-4452 administration, high tumor-specific uptake was observed as early as 15 min and was sustained for all time points assessed (Fig. 1).One hour was chosen as the optimal time point on the basis of central reader visual assessment of image quality, visualization of all lesions, and heterogeneity in tumor uptake (Fig. 2).Among all lesions, 17 metastases in bone, lymph nodes, lungs, pancreas, and parotid glands were not readily identifiable by conventional imaging (Fig. 3; Table 1).Low renal parenchymal uptake enabled identification of renal tumors.SUV max 1 h after administration across 36 lesions ranged from 6.8 to 211.6 (mean, 64.6 [SD, 54.8]) (Table 2).In patients 1, 2, and 3, the highest SUV max was 109, 106, and 212, respectively, whereas the highest SUV mean was 39, 62, and 89, respectively.
[ 68 Ga]Ga-DPI-4452 blood activity concentration rapidly decreased over time; more than 80% of the total administered radioactivity cleared from the bloodstream within 1 h (Supplemental Fig. 2).The average percentage of the injected dose found in urine ranged from 6.1 (SD, 3.6) to 13.3 (SD, 4.5) across the intervals of 0-1.5 h and 1.5-6 h (Supplemental Fig. 3).
No clinically significant toxicity was observed; treatmentemergent adverse events (headache and increased blood creatine kinase [1 each; 33.3%]) were not causally related to [ 68 Ga]Ga-DPI-4452.No significant changes in vital signs, laboratory assessments, or electrocardiograms were observed.

DISCUSSION
[ 68 Ga]Ga-DPI-4452 administration in patients with ccRCC offered outstanding imaging from the earliest (15 min) time point, with sustained tumor uptake up to 4 h and rapid systemic elimination.This is consistent with a nonclinical evaluation of radiolabeled DPI-4452 in which sustained tumor retention (#48 h after administration) of 111 In-labeled-DPI-4452 in mice bearing CAIX-positive tumors was observed (15).
PET revealed an exceptionally high tumor-to-background ratio, with background tissues nearly invisible.One-hour after administration was the optimal time point for lesion assessment; this is substantially shorter than the 3-7 d needed with [ 89 Zr]Zr-girentuximab in the phase 3 ZIRCON study (11).[ 68 Ga]Ga-DPI-4452 also identified 17 metastatic lesions not found with conventional imaging.

CONCLUSION
[ 68 Ga]Ga-DPI-4452 can rapidly provide exceptional images in patients with ccRCC without clinically significant toxicity.High SUVs and tumor-to-background ratios suggest potential for use in both diagnostics and patient selection.These first-in-human findings with radiolabeled DPI-4452 are encouraging for the subsequent evaluation of [ 177 Lu]Lu-DPI-4452 treatment.

FIGURE 1 .
FIGURE 1. Whole-body maximum-intensity projections over time after [ 68 Ga]Ga-DPI-4452 administration.(A) Representative PET images at 4 postadministration time points.(B) PET/CT image at 1 h to allow visualization of anatomic contour.

FIGURE 2 .
FIGURE 2. Whole-body maximum-intensity PET projections from 3 patients with ccRCC 1 h after administration of [ 68 Ga]Ga-DPI-4452.High tumor-to-background contrast is seen, with background physiologic uptake in stomach, small bowel, and bladder.Partially transparent maximum-intensity projections of corresponding CT scans are overlaid on PET images to allow visualization of anatomic contour.

TABLE 1
Comparison of PET with PET/CT 1 Hour After [ 68 Ga]Ga-DPI-4452 Administration

TABLE 2
Lesion Uptake of [ 68 Ga]Ga-DPI-4452 by Tumor Location 1 Hour After Administration *One additional lesion was found with CT imaging only.NA 5 not applicable.Data in parentheses are ranges.