Theranostic GPA33-Pretargeted Radioimmunotherapy of Human Colorectal Carcinoma with a Bivalent 177 Lu-Labeled Radiohapten

• Published in: Journal of Nuclear Medicine Vol. 65; no. 10; pp. 1611 - 1618
• Main Authors: Vaughn, Brett A, Lee, Sang-Gyu, Vargas, Daniela Burnes, Seo, Shin, Rinne, Sara S, Xu, Hong, Guo, Hong-Fen, Le Roux, Alexandre B, Gajecki, Leah, Krebs, Simone, Yang, Guangbin, Ouerfelli, Ouathek, Zanzonico, Pat B, Fung, Edward K, St Jean, Samantha, Carrasco, Sebastian E, Jungbluth, Achim, Cheung, Nai Kong V, Larson, Steven M, Veach, Darren R, Cheal, Sarah M
• Format: Journal Article
• Language: English
• Published: United States 01.10.2024
• Subjects: multivalent; pretargeted radioimmunotherapy; colorectal cancer; GPA33; 177Lu
• ISSN: 0161-5505; 1535-5667; 2159-662X
• DOI: 10.2967/jnumed.124.267685

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 Lu 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. Gemini was synthesized by linking 2 -2-(4-isothiocyanatobenzyl)-DOTA molecules together via a 1,14-diamino-PEG4 linker. [ Lu]Lu-Gemini was prepared with no-carrier-added LuCl to a molar-specific activity of 123 GBq/μmol and radiochemical purity of more than 99%. The specificity of BsAb- Lu-Gemini was verified in vitro. Subsequently, we evaluated biodistribution and whole-body clearance for [ Lu]Lu-Gemini and, for comparison, our gold-standard monovalent [ Lu]Lu- -2-(4-aminobenzyl)-DOTA ([ Lu]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 [ Lu]Lu-Gemini) in mouse models. Initial in vivo studies showed that [ Lu]Lu-Gemini behaved similarly to [ Lu]Lu-DOTA-Bn, with almost identical blood and whole-body clearance kinetics, as well as biodistribution and mouse kidney dosimetry. Pretargeting [ Lu]Lu-Gemini to GPA33-expressing SW1222 human colorectal xenografts was highly effective, leading to absorbed doses of [ Lu]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 [ Lu]Lu-Gemini in DOTA-PRIT leads to improved TIs and augmented [ Lu]Lu-Gemini tumor uptake and retention in comparison to monovalent [ Lu]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 [ Lu]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). We have developed a bivalent DOTA-radiohapten, [ Lu]Lu-Gemini, that showed improved radiopharmacology for DOTA-PRIT application. The use of bivalent [ Lu]Lu-Gemini in DOTA-PRIT, as opposed to monovalent [ Lu]Lu-DOTA-Bn, allows curative treatments with considerably less administered Lu activity while still achieving high TIs for both the blood (>100) and the kidneys (>30).