Proof of Therapeutic Efficacy of a Novel ¹⁷⁷Lu-Labeled Neurotensin Receptor 1-Antagonist in a Colon Carcinoma Xenograft Model

Abstract

Purpose: Increased expression of neurotensin receptor 1 (NTR1) has been shown in a large number of tumor entities like pancreatic or colon carcinoma. Hence, this receptor is a promising target for diagnostic imaging and radioligand therapy (RLT). Based on favorable biodistribution data of the NTR1-targeting agent ¹¹¹In-3BP 227, we investigated the therapeutic effect of its ¹⁷⁷Lu-labeled analog on the tumor growth of NTR1-positive HT29 colon carcinoma xenografts. Methods: 3BP 227 was labeled with ¹⁷⁷Lu. To assess its biodistribution properties, single photon emission computer tomography (SPECT) and computed tomography (CT) scans of HT29-xenografted nude mice injected with ¹⁷⁷Lu-3BP-227 were acquired and ex vivo tissue activity was determined. To evaluate therapeutic efficacy, two groups of mice received the radiopharmaceutical either in a median dose of 165 MBq (129-232 MBq, n = 10) or 110 MBq (82-116 MBq, n = 10), whereas control mice were injected with vehicle (n = 10). Tumor sizes and body weights were monitored for up to 49 days. Renal function and histological morphology were evaluated. Results: Whole-body SPECT/CT images allowed clear tumor visualization with low background activity and high tumor-to-kidney and -liver ratios. Ex vivo biodistribution data confirmed high and persistent uptake of ¹⁷⁷Lu-3BP-227 in HT29 tumors (19.0 ± 3.6 vs. 2.7 ± 1.6 %ID/g at 3 and 69 h p.i., respectively). The application of ¹⁷⁷Lu-3BP-227 resulted in a distinct delay of tumor growth. Median tumor doubling time for controls was 5.5 (2.8; 7.0) days, compared to 17.5 (5.5; 22.5) days for the 110 MBq and 41.0 (27.5; 55.0) days for the 165 MBg group. Compared to controls, median relative tumor volume at day 23 p.i. was reduced by 55% (P = 0.034) in the 110 MBq and by 88% (P < 0.01) in the 165 MBq group. Renal histology and clinical chemistry results did not differ between radiotherapy groups and controls, suggesting absence of therapy-induced acute renal damage. Conclusion: These data demonstrate that the novel NTR1-targeting, theranostic agent 3BP-227 is an effective and promising candidate for RLT with a favorable preliminary safety profile and high potential for clinical translation.