PT  - JOURNAL ARTICLE
AU  - Vaughn, Brett
AU  - Veach, Darren
AU  - Burnes Vargas, Daniela
AU  - Seo, Shin
AU  - Punzalan, Blesida
AU  - Zanzonico, Pat
AU  - Xu, Hong
AU  - Guo, Hong-fen
AU  - Yang, Guangbin
AU  - Ouerfelli, Ouathek
AU  - Cheung, Nai-Kong
AU  - Larson, Steven
AU  - Cheal, Sarah
TI  - <strong>Establishment of efficacy of DOTA-based pretargeted radioimmunotherapy with a bivalent radiohapten for enhanced therapeutic indices</strong>
DP  - 2022 Aug 01
TA  - Journal of Nuclear Medicine
PG  - 2881--2881
VI  - 63
IP  - supplement 2
4099  - http://jnm.snmjournals.org/content/63/supplement_2/2881.short
4100  - http://jnm.snmjournals.org/content/63/supplement_2/2881.full
SO  - J Nucl Med2022 Aug 01; 63
AB  - 2881 Introduction: Based on our previous work with a 1,4,7,10-tetraazacyclododecane-N, N’, N’’, N’’’-tetraacetic acid (DOTA)-based pretargeted radioimmunotherapy (PRIT) platform with monovalent DOTA-haptens, we are currently developing a novel bivalent radiohapten class to achieve improved therapeutic indices (TIs) via cooperative binding at intratumoral bispecific anti-tumor/anti-DOTA antibody (BsAb). We recently established a lead 177Lu-"gemini" precursor consisting of two benzyl-DOTA molecules together via a homobifunctional bis-PEG4-NH2 linker and determined an optimized dosing regimen for 177Lu-gemini 177Lu-PRIT targeting GPA33 tumor antigen (expressed on >95% of human colon cancers). Based on serial biodistribution studies in GPA33-expressing subcutaneous SW1222 human colorectal xenograft-bearing nude mice, preliminary absorbed doses to tumor, blood, and kidney were 455 cGy/MBq, 3.99 cGy/MBq (TI = 114), and 14.0 cGy/MBq (TI = 33), respectively. Herein we report preliminary efficacy and toxicity studies guided by this dosimetry. Methods: 177Lu-gemini was prepared with n.c.a. 177LuCl3 to a specific activity of 141 MBq/nmol and radiochemical purity of >99%. BsAb-177Lu-gemini specificity was verified in vitro. For 177Lu-gemini 177Lu-PRIT, groups (n = 4-5/group) of SW1222-tumor bearing mice (approximate starting tumor volumes: 33 mm3) were injected intravenously in the tail vein: 250 µg (1.19 nmol) of anti-GPA33/anti-DOTA BsAb huA33-huC825, followed 44 h later with 25 µg (2.76 nmol) of dendrimer-clearing agent, and after an additional 4 h, 177Lu-gemini was administered (44.4 MBq/200 pmol). Controls included no treatment and non-specific 177Lu-gemini 177Lu-PRIT (i.e., anti-GD2/anti-DOTA BsAb hu3F8-huC825 in place of anti-GPA33 BsAb). At 24 h post-injection of 177Lu-gemini, randomly selected mice undergoing 177Lu-gemini 177Lu-PRIT were imaged by SPECT/CT to verify tumor targeting (n = 3 of GPA33 177Lu-gemini 177Lu-PRIT and n = 2 of non-specific 177Lu-gemini 177Lu-PRIT). Body weights and tumor volumes were measured before the injection and up to twice per week post-injection. The tumor volume was determined using ellipsoid volume formula (V=4/3π(length/2×width/2×height/2), with dimensions in millimeters.Results: All treatments were well tolerated, with no groups showing average weight loss greater than 15% within 18 days post-injection of 177Lu-gemini. Hematology (WBC:PLT:NEUT x 103/µL) analysis revealed myelosuppression in non-specific 177Lu-gemini 177Lu-PRIT (1.13±0.58:458±327:0.62±0.31) versus baseline (5.54±1.83: 1031±134:1.69±0.42) and GPA33 177Lu-gemini 177Lu-PRIT (5.58±1.60:861±120:1.70±0.31). Notably, no significant differences were observed for WBC, PLT, or NEUT between no treatment and GPA33 177Lu-gemini 177Lu-PRIT. Highly efficient tumor targeting during GPA33 177Lu-gemini 177Lu-PRIT was documented during SPECT/CT imaging, with ROIs of 16.8 ID/cc and corresponding tumor-to-tissue ratios of 32.9, 20.2, 58.3, for heart, kidney, and bone, respectively. While negligible tumor targeting was observed in mice treated with non-specific 177Lu-gemini 177Lu-PRIT, enhanced blood pool activity was evident. ROIs of 1.9 ID/cc and corresponding tumor-to-tissue ratios of 0.4, 1.5, 1.4, for heart, kidney, and bone, respectively were observed. As of 31 days post-injection of 177Lu-gemini, 0/4 and 4/5 of no treatment and non-specific 177Lu-PRIT are still being monitored (average tumor volumes of 189 mm3). For GPA33 177Lu-PRIT, 5/5 remain on study (3/5 have a tumor volume below the measurement threshold of 4.2 mm3, 2/5 have an average tumor volume of 7.3 mm3). Survivors at 150 days will be submitted for necropsy and histopathology evaluation.Conclusions: Substantial tumor regression but no evidence of acute toxicity were observed following administration of GPA33 177Lu-gemini 177Lu-PRIT, suggesting MTD has not been reached and further dose escalation is feasible. GPA33 177Lu-gemini 177Lu-PRIT is a promising theranostic treatment approach for human colorectal cancer