212Pb-Pretargeted Theranostics for Pancreatic Cancer

Abstract

Although pancreatic ductal adenocarcinoma (PDAC) is associated with limited treatment options and poor patient outcomes, targeted α-particle therapy (TAT) represents a promising development in the field. TAT shows potential in treating metastatic cancers, including those that have become resistant to conventional treatments. Among the most auspicious radionuclides stands the in vivo α-generator ²¹²Pb. Combined with the imaging-compatible radionuclide ²⁰³Pb, this theranostic match is a promising modality rapidly translating into the clinic. Methods: Using the pretargeting approach between a radiolabeled 1,2,4,5-tetrazine (Tz) tracer and a trans-cyclooctene (TCO) modified antibody, imaging and therapy with radiolead were performed on a PDAC tumor xenograft mouse model. For therapy, 3 cohorts received a single administration of 1.1, 2.2, or 3.7 MBq of the pretargeting agent, [²¹²Pb]Pb-DO3A-PEG₇-Tz, whereby administered activity levels were guided by dosimetric analysis. Results: The treated mice were holistically evaluated; minimal-to-mild renal tubular necrosis was observed. At the same time, median survival doubled for the highest-dose cohort (10.7 wk) compared with the control cohort (5.1 wk). Conclusion: This foundational study demonstrated the feasibility and safety of pretargeted TAT with ²¹²Pb in PDAC while considering dose limitations and potential adverse effects.

Keywords: lead-203; lead-212; pretargeting; progeny release; targeted α-therapy.

Graphical abstract

FIGURE 1.

Pretargeting with theranostic pair ²⁰³Pb and ²¹²Pb. (Left) Decay scheme of in vivo α-generator ²¹²Pb and SPECT-compatible nuclide ²⁰³Pb. (Right) Illustration of theranostic pretargeting approach, following concept of reference . This figure was created with BioRender. EC = electron capture; t_1/2 = half-life.

FIGURE 2.

Chemical evaluation of Tz compounds. (A) Chemical structures of 4 Tz precursors. (B) Autoradiogram of paper electrophoresis performed with ²¹²Pb-labeled Tz precursors and [²¹²Pb]PbCl₂ at pH 7.4. (C) Normalized high-performance liquid chromatography diagrams of free and ^natPb-labeled Tz compounds (ultraviolet/visible light signal recorded at 254 nm). (D) Radiochemical conversion of Tz precursors (concentration of Tz = 10⁻⁶ mol/L, at 37°C) with ²⁰³Pb measured via radio–instant thin-layer chromatography.

FIGURE 3.

Pretargeting study with [²⁰³Pb]Pb-DO3A-PEG₇-Tz. (A) Biodistribution data of 4 ²⁰³Pb-labeled Tz tracers (2 nmol, 0.7 MBq) in healthy female nude mice. (B) Results of initial pretargeting study, with study design shown at top and, at bottom, biodistribution data of [²⁰³Pb]Pb-DO3A-PEG₇-Tz (2 nmol, 0.7 MBq) in mice pretargeted with 5B1-TCO (100 μg, 0.7 nmol), accompanied by SPECT maximum-intensity projections (2 nmol, 18.5 MBq). Bl = bladder uptake; T = tumor uptake.

FIGURE 4.

²¹²Bi release and dosimetry estimations. (Top) Biodistribution data of ²¹²Bi, measured 15 min after death, and of ²¹²Pb. (Bottom) Estimated relative biological effectiveness–weighted absorbed dose coefficients for [²¹²Pb]Pb-DO3A-PEG7-Tz (in Gy-equivalent per MBq administered) estimated for different assumptions regarding redistribution of ²¹²Pb’s progeny.

FIGURE 5.

Therapy study: pretargeting with [²¹²Pb]Pb-DO3A-PEG₇-Tz. (A) Cerenkov luminescence imaging of 4 arms that received [²¹²Pb]Pb-DO3A-PEG₇-Tz (2 nmol) via pretargeting 24 h after injection. (B) Maximum-intensity projections (24 h after injection) of 4 mice (3.7-MBq cohort) injected with [⁶⁴Cu]Cu-DO3A-PEG₇-Tz 1 d after therapy to demonstrate complementary PET imaging. (C) Waterfall plot of fold change of tumor volume for each cohort. (D) Survival probability as function of time after Tz injection (n = 8 per cohort). Bl = bladder uptake; K = kidney uptake; T = tumor uptake.

FIGURE 6.

Representative histology results. Representative histology of hematoxylin- and eosin-stained kidney (top) and ovarian (bottom) sections of BxPC-3 tumor–bearing female athymic nude mice. (Left) Mice treated with ²¹²Pb. (Right) Control group. Histopathology of kidneys revealed multifocal, minimal-to-mild tubular injury (arrows) affecting approximately 1%–10% of tubules. Control animals showed histologically normal kidneys. Histopathology of treated ovaries revealed diffuse marked ovarian atrophy with complete loss of follicles and corpora lutea.