Theranostic GPA33-pretargeted radioimmunotherapy of human colorectal carcinoma with a bivalent (177)Lu-labeled radiohapten Journal Article
| Authors: | Vaughn, B. A.; Lee, S. G.; Vargas, D. B.; Seo, S.; Rinne, S. S.; Xu, H.; Guo, H. F.; Le Roux, A. B.; Gajecki, L.; Krebs, S.; Yang, G.; Ouerfelli, O.; Zanzonico, P. B.; Fung, E. K.; St Jean, S.; Carrasco, S. E.; Jungbluth, A.; Cheung, N. K. V.; Larson, S. M.; Veach, D. R.; Cheal, S. M. |
| Article Title: | Theranostic GPA33-pretargeted radioimmunotherapy of human colorectal carcinoma with a bivalent (177)Lu-labeled radiohapten |
| Abstract: | Radiolabeled small-molecule DOTA-haptens can be combined with antitumor/anti-DOTA bispecific antibodies (BsAbs) for pretargeted radioimmunotherapy (PRIT). For optimized delivery of the theranostic γ- and β-emitting isotope 177Lu with DOTA-based PRIT (DOTA-PRIT), bivalent Gemini (DOTA-Bn-thiourea-PEG4-thiourea-Bn-DOTA, aka (3,6,9,12-tetraoxatetradecane-1,14-diyl)bis(DOTA-benzyl thiourea)) was developed. Methods: Gemini was synthesized by linking 2 S-2-(4-isothiocyanatobenzyl)-DOTA molecules together via a 1,14-diamino-PEG4 linker. [177Lu]Lu-Gemini was prepared with no-carrier-added 177LuCl3 to a molar-specific activity of 123 GBq/μmol and radiochemical purity of more than 99%. The specificity of BsAb-177Lu-Gemini was verified in vitro. Subsequently, we evaluated biodistribution and whole-body clearance for [177Lu]Lu-Gemini and, for comparison, our gold-standard monovalent [177Lu]Lu-S-2-(4-aminobenzyl)-DOTA ([177Lu]Lu-DOTA-Bn) in naïve (tumor-free) athymic nude mice. For our proof-of-concept system, a 3-step pretargeting approach was performed with an established DOTA-PRIT regimen (anti-GPA33/anti-DOTA IgG-scFv BsAb, a clearing agent, and [177Lu]Lu-Gemini) in mouse models. Results: Initial in vivo studies showed that [177Lu]Lu-Gemini behaved similarly to [177Lu]Lu-DOTA-Bn, with almost identical blood and whole-body clearance kinetics, as well as biodistribution and mouse kidney dosimetry. Pretargeting [177Lu]Lu-Gemini to GPA33-expressing SW1222 human colorectal xenografts was highly effective, leading to absorbed doses of [177Lu]Lu-Gemini for blood, tumor, liver, spleen, and kidneys of 3.99, 455, 6.93, 5.36, and 14.0 cGy/MBq, respectively. Tumor-to-normal tissue absorbed-dose ratios (i.e., therapeutic indices [TIs]) for the blood and kidneys were 114 and 33, respectively. In addition, we demonstrate that the use of bivalent [177Lu]Lu-Gemini in DOTA-PRIT leads to improved TIs and augmented [177Lu]Lu-Gemini tumor uptake and retention in comparison to monovalent [177Lu]Lu-DOTA-Bn. Finally, we established efficacy in SW1222 tumor-bearing mice, demonstrating that a single injection of anti-GPA33 DOTA-PRIT with 44 MBq (1.2 mCi) of [177Lu]Lu-Gemini (estimated tumor-absorbed dose, 200 Gy) induced complete responses in 5 of 5 animals and a histologic cure in 2 of 5 (40%) animals. Moreover, a significant increase in survival compared with nontreated controls was noted (maximum tolerated dose not reached). Conclusion: We have developed a bivalent DOTA-radiohapten, [177Lu]Lu-Gemini, that showed improved radiopharmacology for DOTA-PRIT application. The use of bivalent [177Lu]Lu-Gemini in DOTA-PRIT, as opposed to monovalent [177Lu]Lu-DOTA-Bn, allows curative treatments with considerably less administered 177Lu activity while still achieving high TIs for both the blood (>100) and the kidneys (>30). © 2024 by the Society of Nuclear Medicine and Molecular Imaging. |
| Keywords: | radiopharmaceuticals; colorectal cancer; mouse; animal; animals; mice; radiotherapy; cell line, tumor; diagnostic imaging; colorectal neoplasms; chemistry; isotope labeling; tissue distribution; membrane glycoproteins; colorectal tumor; membrane protein; tumor cell line; radiopharmaceutical agent; radioisotope; radioimmunotherapy; radioisotopes; single heterocyclic rings; heterocyclic compounds, 1-ring; lutetium; procedures; pretargeted radioimmunotherapy; lutetium-177; humans; human; female; gpa33 protein, human; multivalent; 177lu; gpa33; theranostic nanomedicine |
| Journal Title: | Journal of Nuclear Medicine |
| Volume: | 65 |
| Issue: | 10 |
| ISSN: | 0161-5505 |
| Publisher: | Society of Nuclear Medicine |
| Date Published: | 2024-10-01 |
| Start Page: | 1611 |
| End Page: | 1618 |
| Language: | English |
| DOI: | 10.2967/jnumed.124.267685 |
| PUBMED: | 39168519 |
| PROVIDER: | scopus |
| PMCID: | PMC11448610 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work