177Lu-PSMA-617 Therapy in Mice, with or without the Antioxidant α1-Microglobulin (A1M), Including Kidney Damage Assessment Using 99mTc-MAG3 Imaging

Abstract

Anti-prostate specific membrane antigen (PSMA) radioligand therapy is promising but not curative in castration resistant prostate cancer. One way to broaden the therapeutic index could be to administer higher doses in combination with radioprotectors, since administered radioactivity is kept low today in order to avoid side-effects from a high absorbed dose to healthy tissue. Here, we investigated the human radical scavenger α1-microglobulin (A1M) together with 177-Lutetium (177Lu) labeled PSMA-617 in preclinical models with respect to therapeutic efficacy and kidney toxicity. Nude mice with subcutaneous LNCaP xenografts were injected with 50 or 100 MBq of [177Lu]Lu-PSMA-617, with or without injections of recombinant A1M (rA1M) (at T = 0 and T = 24 h). Kidney absorbed dose was calculated to 7.36 Gy at 4 days post a 100 MBq injection. Activity distribution was imaged with Single-Photon Emission Computed Tomography (SPECT) at 24 h. Tumor volumes were measured continuously, and kidneys and blood were collected at termination (3–4 days and 3–4 weeks after injections). In a parallel set of experiments, mice were given [177Lu]Lu-PSMA-617 and rA1M as above and dynamic technetium-99m mercaptoacetyltriglycine ([99mTc]Tc-MAG3) SPECT imaging was performed prior to injection, and 3- and 6-months post injection. Blood and urine were continuously sampled. At termination (6 months) the kidneys were resected. Biomarkers of kidney function, expression of stress genes and kidney histopathology were analyzed. [177Lu]Lu-PSMA-617 uptake, in tumors and kidneys, as well as treatment efficacy did not differ between rA1M and vehicle groups. In mice given rA1M, [99mTc]Tc-MAG3 imaging revealed a significantly higher slope of initial uptake at three months compared to mice co-injected with [177Lu]Lu-PSMA-617 and vehicle. Little or no change compared to control was seen in urine albumin, serum/plasma urea levels, RT-qPCR analysis of stress response genes and in the kidney histopathological evaluation. In conclusion, [99mTc]Tc-MAG3 imaging presented itself as a sensitive tool to detect changes in kidney function revealing that administration of rA1M has a potentially positive effect on kidney perfusion and tubular function when combined with [177Lu]Lu-PSMA-617 therapy. Furthermore, we could show that rA1M did not affect anti-PSMA radioligand therapy efficacy.

Evaluation of the PSMA-Binding Ligand 212Pb-NG001 in Multicellular Tumour Spheroid and Mouse Models of Prostate Cancer

“…The standard strategy to avoid kidney damage in clinical targeted radionuclide therapy is to ensure that the patient is well hydrated and to co-infuse the basic amino acids lysine and arginine to reduce renal retention of the radioligands [ 41 , 46 , 47 ]. In addition, several strategies to reduce kidney toxicity are currently under investigation, including dose fractionation and co-injection with cold PSMA ligand, succinylated gelatin or radioprotectors, such as α1-microglobulin or amifostine [ 41 , 48 , 49 , 50 , 51 , 52 , 53 ].…”

Kidney Protection with the Radical Scavenger α1-Microglobulin (A1M) during Peptide Receptor Radionuclide and Radioligand Therapy

“…A general decline of these parameters over time was reported, comparing three and six months with baseline. However, the decline seen at three months was less in animals receiving A1M (5 mg/kg with additional 5 mg/kg after 24 h), suggesting that A1M protected the kidneys at medium term; however, the protective effect was not evident after six months [ 130 ].…”

“…In the same study, the potential interference of A1M with tumor treatment was investigated in nude mice with subcutaneous LNCaP xenografts [ 130 ]. Quantification of 177 Lu-PSMA-617 in tumors from SPECT/CT imaging showed no significant differences between animals with or without co-injections of A1M.…”

“…Therefore, a radioprotector such as A1M could be of potential use. In a recent study, ([ 99m Tc]Tc-MAG3) SPECT imaging was used to evaluate kidney function after 177 Lu-PSMA-617 (100 or 50 MBq) injections in male BALB/cAnNRj mice [130]. From the resulting renogram, perfusion, uptake, and excretion of the radiotracer can be analyzed, as previously reported in a kidney mouse model of unilateral ureteral obstruction [131].…”

Hematological Toxicity in Mice after High Activity Injections of 177Lu-PSMA-617

“…Relevant animal models are needed to evaluate efficacy and toxicity to enable optimization of RLT alone or in combination with other therapies, for example, chemotherapy, inhibitors of DNA damage repair, or radiosensitizers (reviewed in [11]). Moreover, therapy combinations, e.g., infusion of amino acids, PSMA inhibitors, and α 1 -microglobulin (A1M), may be aimed at reducing radiation-related side-effects [12][13][14][15]. Our group has focused on the use of A1M, an antioxidant with radical scavenging, reductase, and hemebinding abilities (reviewed in [16]).…”