CMR 2005: 3.09: Preclinical efficacy of ¹⁷⁷Lu‐AMBA, a radiotherapeutic targeting the GRP receptor

Abstract

Tween-20 and injected intravenously into patients with advanced NSCLC. Following intravenous injection of 131 I-labeled NM404 ( < 1 mCi), patients with advanced NSCLC were scanned at 3, 6, 24, 48 and 96 h and at 11 days on a GE Maxxus dual-head SPECT imaging system. Blood and urine samples were collected and analyzed at various times over 7 days and again at 30 days (blood only) after injection of NM404. Results: Initial qualitative imaging results from seven patients indicate that 131 I-labeled NM404 clearly localizes in pulmonary masses as early as 6 h after injection and is selectively retained in these tumors in excess of 11 days. Quantitative results, including dosimetry determination, are in progress. From a tolerability perspective, no symptoms or changes in vital signs or physical examination were observed after injection of radiolabeled NM404. Mild changes in blood counts, electrolytes and lipids which were observed were not clinically significant and all resolved within a matter of days. Conclusions: These preliminary findings suggest that NM404 is well tolerated and exhibits similar tumor uptake and retention properties in human NSCLC as seen previously in rodent tumor models. In order to evaluate its true promise as an imaging agent, however, we recently radiolabeled NM404 in >60% isolated yield with commercial iodine-124 (Eastern Isotopes), a new PET isotope with a 4-day half-life, and have recently acquired beautiful microPET images in several rodent tumor models as a prelude to upcoming human PET imaging studies in a variety of cancer types CMR 2005: 3.09 Preclinical efficacy of 177 Lu-AMBA, a radiotherapeutic targeting the GRP receptor Rationale and Objectives: We are developing 177 Lu-AMBA ( 177 Lu-DO3A-CH 2 CO-G-4-aminobenzoyl-QWAVGHLM-NH 2 ), a gastrinreleasing peptide receptor (GRP) agonist, for use as a radiotherapeutic. The preclinical studies reported here characterize its efficacy in mice including long-term, multidose therapeutic studies in a human prostate tumor xenograft model. This compound targets two of the receptors of the GRP-R family, which are upregulated in several human cancers. Methods: Biodistributions were performed in the PC-3 (human metastatic prostate carcinoma, bone) tumor-bearing male nude [Tac:Cr:(NCr)-Fox1 nu ] mouse model using 5 mCi of 177 Lu-AMBA, administered i.v., after 1 and 24 h. Radiotherapy studies with 177 Lu-AMBA were also conducted in the PC-3 model (starting tumor size 95 mm 3 ): administered 30 mCi/kg, s.c, single dose (n ¼ 32) or two equal doses administered at 0 and 14 days (n ¼ 36) or vehicle control s.c. (n ¼ 16). The mice were followed up to 120 days; necropsy was performed with tumors and organs collected for histology. Results: Renal excretion was predominant with only 4.4% ID/g kidney at 1 h and low retention. Tumor uptake was 6.4% ID/g at 1 h and 3.4% at 24 h. In long-term radiotherapeutic studies, treated mice dramatically outlived control mice. Two-dose mice showed increased tumor growth delay and improved overall survival compared with one-do...

Alpha- versus Beta-Particle Radiopeptide Therapy in a Human Prostate Cancer Model (213Bi-DOTA-PESIN and 213Bi-AMBA versus177Lu-DOTA-PESIN)

“…One important prerequisite for effective multiple dose treatment is a fast recovery from receptor downregulation after treatment. Lantry and colleagues (29) found a fast GRP-R recovery within 1 hour after injection, and in the present study we found no decrease in GRP-R density in recurrent tumor disease. Twenty-one days after initial treatment when only small or micrometastatic disease (0-4.3 mm) was apparent, additional 213 Bi-DOTA-PESIN or 213 Bi-AMBA injections reduced the risk of recurrent disease by 57%.…”

“…Radiolabeling of 177 Lu-DOTA-PESIN and synthesis of DOTA-PESIN and AMBA followed procedures described previously (29,31). 213 Bi was eluted from an 225 Ac/ 213 Bi-generator produced by the Institute for Transuranium Elements, Karlsruhe, Germany, using 600 mL 0.1 mol/L NaI/HCl solution (32,33).…”

“…Importantly, 100% of invasive prostatic carcinomas but not benign prostatic tissue express GRP receptors at a high density, making GRP-R an attractive target for imaging and therapy (23,24). In recent years, several groups have synthesized and evaluated GRP analogues (25-27): Scopinaro and colleagues detected primary prostate cancer in all patients using 99m Tc-labeled bombesin (28), and Lantry and colleagues found a complete response rate of 39% after treatment of PC-3 tumor-bearing mice with 56 MBq (1.5 mCi) 177 Lu-AMBA (29). Despite these promising results, there are potentially limiting factors that have to be taken into account when considering therapeutic applications of GRP analogues.…”

International Union of Pharmacology. LXVIII. Mammalian Bombesin Receptors: Nomenclature, Distribution, Pharmacology, Signaling, and Functions in Normal and Disease States

“…Unfortunately, many common tumors (colon, pancreas, head/ neck, prostate, and lung) may not overexpress somatostatin receptors; however they frequently overexpress Bn receptors, especially the BB 2 receptor Reubi et al, 2002;Moody et al, 2003a;Heuser et al, 2005;Jensen and Moody, 2006;Patel et al, 2006;Fleischmann et al, 2007). This observation has led to considerable interest in the possibility of developing radiolabeled analogs of Bn that could be use for localization of the tumors containing Bn receptors or the development of radiolabeled Bn analogs or Bn analogs coupled to cytotoxic agents that could be used to treat tumors overexpressing Bn receptors through bombesin receptor-mediated cytotoxicity (Breeman et al, 2002;de Jong et al, 2003;Cornelio et al, 2007;de Visser et al, 2007a Tc) GRP analogs with enhanced stability that bind with high affinity to BB 2 receptors have been reported, as well as their ability to image various human tumors in vivo using gamma detectors or positron emission tomography (Breeman et al, 2002;Nock et al, 2003;Smith et al, 2003Smith et al, , 2005Johnson et al, 2006;Lantry et al, 2006;Zhang et al, 2006Zhang et al, , 2007ade Visser et al, 2007a;DimitrakopoulouStrauss et al, 2007;Garrison et al, 2007;Parry et al, 2007;Prasanphanich et al, 2007;Waser et al, 2007). In some preliminary studies in humans, tumors were imaged in the majority of patients, and in some cases, tumors that were not seen with other commonly used imaging modalities were detected using radiolabeled Bn analogs Scopinaro et al, 2004Scopinaro et al, , 2005Dimitrakopoulou-Strauss et al, 2007).…”

“…A number of Bn analogs coupled to radiolabeled compounds (e.g., 177 Lu) (Smith et al, 2005;Johnson et al, 2006;Lantry et al, 2006;Zhang et al, 2007a) and to cytotoxic agents (camptothecin, a topoisomerase inhibitor, doxorubicin analogs, and paclitaxel) (Schally and Nagy, 1999;Breeman et al, 2002;Moody et al, , 2006bSchally and Nagy, 2004;Engel et al, 2005;Buchholz et al, 2006;Nanni et al, 2006;Panigone and Nunn, 2006;Safavy et al, 2006;Engel et al, 2007) have been described. These analogs retain their high affinity for Bn receptors and are internalized by Bn receptor-bearing tissues, for the possibility of delivering Bn receptor-mediated tumoral cytotoxicity.…”