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1.
Pharmaceuticals (Basel) ; 17(1)2024 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-38256909

RESUMEN

The use of radionuclides for targeted endoradiotherapy is a rapidly growing field in oncology. In particular, the focus on the biological effects of different radiation qualities is an important factor in understanding and implementing new therapies. Together with the combined approach of imaging and therapy, therapeutic nuclear medicine has recently made great progress. A particular area of research is the use of alpha-emitting radionuclides, which have unique physical properties associated with outstanding advantages, e.g., for single tumor cell targeting. Here, recent results and open questions regarding the production of alpha-emitting isotopes as well as their chemical combination with carrier molecules and clinical experience from compassionate use reports and clinical trials are discussed.

2.
Theranostics ; 13(15): 5469-5482, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37908719

RESUMEN

Rationale: The in vivo dynamics of CAR-T cells remain incompletely understood. Novel methods are urgently needed to longitudinally monitor transferred cells non-invasively for biodistribution, functionality, proliferation, and persistence in vivo and for improving their cytotoxic potency in case of treatment failure. Methods: Here we engineered CD19 CAR-T cells ("Thor"-cells) to express a membrane-bound scFv, huC825, that binds DOTA-haptens with picomolar affinity suitable for labeling with imaging or therapeutic radionuclides. We assess its versatile utility for serial tracking studies with PET and delivery of α-radionuclides to enhance anti-tumor killing efficacy in sub-optimal adoptive cell transfer in vivo using Thor-cells in lymphoma models. Results: We show that this reporter gene/probe platform enables repeated, sensitive, and specific assessment of the infused Thor-cells in the whole-body using PET/CT imaging with exceptionally high contrast. The uptake on PET correlates with the Thor-cells on a cellular and functional level. Furthermore, we report the ability of Thor-cells to accumulate cytotoxic alpha-emitting radionuclides preferentially at tumor sites, thus increasing therapeutic potency. Conclusion: Thor-cells are a new theranostic agent that may provide crucial information for better and safer clinical protocols of adoptive T cell therapies, as well as accelerated development strategies.


Asunto(s)
Antineoplásicos , Radioinmunoterapia , Tomografía Computarizada por Tomografía de Emisión de Positrones , Distribución Tisular , Inmunoterapia Adoptiva/métodos , Radioisótopos/metabolismo , Antineoplásicos/metabolismo , Linfocitos T/metabolismo
3.
J Nucl Med ; 64(9): 1439-1445, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37348919

RESUMEN

Epithelial ovarian cancer (EOC) is often asymptomatic and presents clinically in an advanced stage as widespread peritoneal microscopic disease that is generally considered to be surgically incurable. Targeted α-therapy with the α-particle-emitting radionuclide 225Ac (half-life, 9.92 d) is a high-linear-energy-transfer treatment approach effective for small-volume disease and even single cells. Here, we report the use of human epidermal growth factor receptor 2 (HER2) 225Ac-pretargeted radioimmunotherapy (PRIT) to treat a mouse model of human EOC SKOV3 xenografts growing as peritoneal carcinomatosis (PC). Methods: On day 0, 105 SKOV3 cells transduced with a luciferase reporter gene were implanted intraperitoneally in nude mice, and tumor engraftment was verified by bioluminescent imaging (BLI). On day 15, treatment was started using 1 or 2 cycles of 3-step anti-HER2 225Ac-PRIT (37 kBq/cycle as 225Ac-Proteus DOTA), separated by a 1-wk interval. Efficacy and toxicity were monitored for up to 154 d. Results: Untreated PC-tumor-bearing nude mice showed a median survival of 112 d. We used 2 independent measures of response to evaluate the efficacy of 225Ac-PRIT. First, a greater proportion of the treated mice (9/10 1-cycle and 8/10 2-cycle; total, 17/20; 85%) survived long-term compared with controls (9/27, 33%), and significantly prolonged survival was documented (log-rank [Mantel-Cox] P = 0.0042). Second, using BLI, a significant difference in the integrated BLI signal area to 98 d was noted between controls and treated groups (P = 0.0354). Of a total of 8 mice from the 2-cycle treatment group (74 kBq total) that were evaluated by necropsy, kidney radiotoxicity was mild and did not manifest itself clinically (normal serum blood urea nitrogen and creatinine). Dosimetry estimates (relative biological effectiveness-weighted dose, where relative biological effectiveness = 5) per 37 kBq administered for tumors and kidneys were 56.9 and 16.1 Gy, respectively. One-cycle and 2-cycle treatments were equally effective. With immunohistology, mild tubular changes attributable to α-toxicity were observed in both therapeutic groups. Conclusion: Treatment of EOC PC-tumor-bearing mice with anti-HER2 225Ac-PRIT resulted in histologic cures and prolonged survival with minimal toxicity. Targeted α-therapy using the anti-HER2 225Ac-PRIT system is a potential treatment for otherwise incurable EOC.


Asunto(s)
Neoplasias Peritoneales , Radioinmunoterapia , Humanos , Animales , Ratones , Radioinmunoterapia/métodos , Ratones Desnudos , Neoplasias Peritoneales/diagnóstico por imagen , Neoplasias Peritoneales/radioterapia , Neoplasias Peritoneales/tratamiento farmacológico , Radioisótopos/uso terapéutico , Línea Celular Tumoral
4.
Mol Cancer Res ; 21(4): 307-315, 2023 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-36608299

RESUMEN

Noninvasive biomarkers for androgen receptor (AR) pathway activation are urgently needed to better monitor patient response to prostate cancer therapies. AR is a critical driver and mediator of resistance of prostate cancer but currently available noninvasive prostate cancer biomarkers to monitor AR activity are discordant with downstream AR pathway activity. External beam radiotherapy (EBRT) remains a common treatment for all stages of prostate cancer, and DNA damage induced by EBRT upregulates AR pathway activity to promote therapeutic resistance. [89Zr]11B6-PET is a novel modality targeting prostate-specific protein human kallikrein 2 (hK2), which is a surrogate biomarker for AR activity. Here, we studied whether [89Zr]11B6-PET can accurately assess EBRT-induced AR activity.Genetic and human prostate cancer mouse models received EBRT (2-50 Gy) and treatment response was monitored by [89Zr]11B6-PET/CT. Radiotracer uptake and expression of AR and AR target genes was quantified in resected tissue.EBRT increased AR pathway activity and [89Zr]11B6 uptake in LNCaP-AR and 22RV1 tumors. EBRT increased prostate-specific [89Zr]11B6 uptake in prostate cancer-bearing mice (Hi-Myc x Pb_KLK2) with no significant changes in uptake in healthy (Pb_KLK2) mice, and this correlated with hK2 protein levels. IMPLICATIONS: hK2 expression in prostate cancer tissue is a proxy of EBRT-induced AR activity that can noninvasively be detected using [89Zr]11B6-PET; further clinical evaluation of hK2-PET for monitoring response and development of resistance to EBRT in real time is warranted.


Asunto(s)
Neoplasias de la Próstata , Radioisótopos , Animales , Humanos , Masculino , Ratones , Línea Celular Tumoral , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/radioterapia , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Circonio
5.
Sci Rep ; 12(1): 13034, 2022 07 29.
Artículo en Inglés | MEDLINE | ID: mdl-35906379

RESUMEN

The growing interest and clinical translation of alpha particle (α) therapies brings with it new challenges to assess target cell engagement and to monitor therapeutic effect. Noninvasive imaging has great potential to guide α-treatment and to harness the potential of these agents in the complex environment of disseminated disease. Poly(ADP) ribose polymerase 1 (PARP-1) is among the most abundantly expressed DNA repair enzymes with key roles in multiple repair pathways-such as those induced by irradiation. Here, we used a third-generation PARP1-specific radiotracer, [18F]-PARPZ, to delineate castrate resistant prostate cancer xenografts. Following treatment with the clinically applied [225Ac]-PSMA-617, positron emission tomography was performed and correlative autoradiography and histology acquired. [18F]-PARPZ was able to distinguish treated from control (saline) xenografts by increased uptake. Kinetic analysis of tracer accumulation also suggests that the localization of the agent to sites of increased PARP-1 expression is a consequence of DNA damage response. Together, these data support expanded investigation of [18F]-PARPZ to facilitate clinical translation in the ⍺-therapy space.


Asunto(s)
Radioisótopos de Flúor , Neoplasias de la Próstata , Partículas alfa/uso terapéutico , Humanos , Cinética , Masculino , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/radioterapia , Tomografía Computarizada por Rayos X
6.
Clin Cancer Res ; 28(10): 2030-2037, 2022 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-35247915

RESUMEN

PURPOSE: The anti-CD33 antibody lintuzumab has modest activity against acute myeloid leukemia (AML). To increase its potency, lintuzumab was conjugated to actinium-225 (225Ac), a radionuclide yielding 4 α-particles. This first-in-human, phase I trial was conducted to determine the safety, pharmacology, and biological activity of 225Ac-lintuzumab. PATIENTS AND METHODS: Eighteen patients (median age, 64 years; range, 45-80) with relapsed or refractory AML received a single infusion of 225Ac-lintuzumab at activities of 18.5 to 148 kBq/kg. RESULTS: The maximum tolerated dose was 111 kBq/kg. Dose-limiting toxicities included myelosuppression lasting > 35 days in one patient receiving 148 kBq/kg and death from sepsis in two patients treated with 111 and 148 kBq/kg. Myelosuppression was the most common toxicity. Significant extramedullary toxicities were limited to transient grade 3 liver function abnormalities. Pharmacokinetics were determined by gamma counting serial whole blood, plasma, and urine samples at energy windows for the 225Ac daughters, francium-221 and bismuth-213. Two-phase elimination kinetics were seen with mean plasma t1/2 - α and t1/2 - ß of 1.9 and 38 hours, respectively. Peripheral blood blasts were eliminated in 10 of 16 evaluable patients (63%) but only at doses of ≥ 37 kBq/kg. Bone marrow blasts were reduced in 10 of 15 evaluable patients (67%), including 3 patients with marrow blasts ≤ 5% and one patient with a morphologic leukemia-free state. CONCLUSIONS: Therapy for AML with the targeted α-particle generator 225Ac-lintuzumab was feasible with an acceptable safety profile. Elimination of circulating blasts or reductions in marrow blasts were observed across all dose levels.


Asunto(s)
Inmunoconjugados , Leucemia Mieloide Aguda , Actinio/efectos adversos , Partículas alfa/efectos adversos , Anticuerpos Monoclonales Humanizados , Humanos , Inmunoconjugados/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Persona de Mediana Edad
9.
J Nucl Med Technol ; 50(1): 10-16, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34750237

RESUMEN

CE credit: For CE credit, you can access the test for this article, as well as additional JNMT CE tests, online at https://www.snmmilearningcenter.org Complete the test online no later than March 2025. Your online test will be scored immediately. You may make 3 attempts to pass the test and must answer 75% of the questions correctly to receive Continuing Education Hour (CEH) credit. Credit amounts can be found in the SNMMI Learning Center Activity. SNMMI members will have their CEH credit added to their VOICE transcript automatically; nonmembers will be able to print out a CE certificate upon successfully completing the test. The online test is free to SNMMI members; nonmembers must pay $15.00 by credit card when logging onto the website to take the test.α-emitting radionuclides provide an effective means of delivering large radiation doses to targeted treatment locations. 223RaCl2 is Food and Drug Administration-approved for treatment of metastatic castration-resistant prostate cancer, and 225Ac (225Ac-lintuzumab) radiolabeled antibodies have been shown to be beneficial for patients with acute myeloid leukemia. In recent years, there has been increasing use of α-emitters in theranostic agents with both small- and large-molecule constructs. The proper precautionary means for their use and surveying documentation of these isotopes in a clinical setting are an essential accompaniment to these treatments. Methods: Patient treatment data collected over a 3-y period, as well as regulatory requirements and safety practices, are described. Commonly used radiation instruments were evaluated for their ability to identify potential radioactive material spills and contamination events during a clinical administration of 225Ac. These instruments were placed at 0.32 cm from a 1.0-cm 225Ac disk source for measurement purposes. Radiation background values, efficiencies, and minimal detectable activities were measured and calculated for each type of detector. Results: The median external measured dose rate from 223RaCl2 patients (n = 611) was 2.5 µSv h-1 on contact and 0.2 µSv h-1 at 1 m immediately after administration. Similarly, 225Ac-lintuzumab (n = 19) patients had median external dose rates of 2.0 µSv h-1 on contact and 0.3 µSv h-1 at 1 m. For the measurement of 225Ac samples, a liquid scintillation counter was found to have the highest overall efficiency (97%), whereas a ZnS α-probe offered the lowest minimal detectable activity at 3 counts per minute. Conclusion: In this article, we report data from 630 patients who were undergoing treatment with the α-emitting isotopes 223Ra and 225Ac. Although α-emitters have the ability to deliver a higher internal radiation dose to the exposed tissues than can other unsealed radionuclides, they typically present minimal concerns about external dose rate. Additionally, α-radiation can be efficiently detected with appropriate radiation instrumentation, such as a liquid scintillation counter or ZnS probe, which should be prioritized when surveying for spills of α-emitters.


Asunto(s)
Neoplasias de la Próstata , Radioisótopos , Humanos , Masculino , Radioisótopos/uso terapéutico
10.
Bioconjug Chem ; 32(4): 649-654, 2021 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-33819023

RESUMEN

Pretargeted imaging and radioimmunotherapy approaches are designed to have superior targeting properties over directly targeted antibodies but impose more complex pharmacology, which hinders efforts to optimize the ligands prior to human applications. Human embryonic kidney 293T cells expressing the humanized single-chain variable fragment (scFv) C825 (huC825) with high-affinity for DOTA-haptens (293T-huC825) in a transmembrane-anchored format eliminated the requirement to use other pretargeting reagents and provided a simplified, accelerated assay of radiohapten capture while offering normalized cell surface expression of the molecular target of interest. Using binding assays, ex vivo biodistribution, and in vivo imaging, we demonstrated that radiohaptens based on benzyl-DOTA and a second generation "Proteus" DOTA-platform effectively and specifically engaged membrane-bound huC825, achieving favorable tumor-to-normal tissue uptake ratios in mice. Furthermore, [86Y]Y-DOTA-Bn predicted absorbed dose to critical organs with reasonable accuracy for both [177Lu]Lu-DOTA-Bn and [225Ac]Ac-Pr, which highlights the benefit of a dosimetry-based treatment approach.


Asunto(s)
Ingeniería Celular , Haptenos , Radioinmunoterapia/métodos , Radiofármacos/química , Animales , Autorradiografía , Células HEK293 , Humanos , Ratones , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos/farmacocinética , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Clin Cancer Res ; 27(7): 2050-2060, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33441295

RESUMEN

PURPOSE: Most patients with prostate cancer treated with androgen receptor (AR) signaling inhibitors develop therapeutic resistance due to restoration of AR functionality. Thus, there is a critical need for novel treatment approaches. Here we investigate the theranostic potential of hu5A10, a humanized mAb specifically targeting free PSA (KLK3). EXPERIMENTAL DESIGN: LNCaP-AR (LNCaP with overexpression of wildtype AR) xenografts (NSG mice) and KLK3_Hi-Myc transgenic mice were imaged with 89Zr- or treated with 90Y- or 225Ac-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma counting, PET, autoradiography, and microscopy. Therapeutic efficacy of [225Ac]hu5A10 and [90Y]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [89Zr]hu5A10 in nonhuman primates (NHP) were determined using PET. RESULTS: Biodistribution of radiolabeled hu5A10 constructs was comparable in different mouse models. Specific tumor uptake increased over time and correlated with PSA expression. Treatment with [90Y]/[225Ac]hu5A10 effectively reduced tumor burden and prolonged survival (P ≤ 0.0054). Effects of [90Y]hu5A10 were more immediate than [225Ac]hu5A10 (TTN, P < 0.0001) but less sustained (TTP, P < 0.0001). Complete responses were observed in 7 of 18 [225Ac]hu5A10 and 1 of 9 mice [90Y]hu5A10. Pharmacokinetics of [89Zr]hu5A10 were consistent between NHPs and comparable with those in mice. [89Zr]hu5A10-PET visualized the NHP-prostate over the 2-week observation period. CONCLUSIONS: We present a complete preclinical evaluation of radiolabeled hu5A10 in mouse prostate cancer models and NHPs, and establish hu5A10 as a new theranostic agent that allows highly specific and effective downstream targeting of AR in PSA-expressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating prostate cancer.


Asunto(s)
Partículas alfa/uso terapéutico , Partículas beta/uso terapéutico , Electrones/uso terapéutico , Antígeno Prostático Específico/inmunología , Neoplasias de la Próstata/radioterapia , Radioinmunoterapia/métodos , Animales , Modelos Animales de Enfermedad , Transferencia Lineal de Energía , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos BALB C , Tomografía de Emisión de Positrones , Antígeno Prostático Específico/metabolismo , Receptores Androgénicos/fisiología , Distribución Tisular
12.
Sci Rep ; 11(1): 157, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33420138

RESUMEN

Cellulose nanocrystals (CNC) are linear organic nanomaterials derived from an abundant naturally occurring biopolymer resource. Strategic modification of the primary and secondary hydroxyl groups on the CNC introduces amine and iodine group substitution, respectively. The amine groups (0.285 mmol of amine per gram of functionalized CNC (fCNC)) are further reacted with radiometal loaded-chelates or fluorescent dyes as tracers to evaluate the pharmacokinetic profile of the fCNC in vivo. In this way, these nanoscale macromolecules can be covalently functionalized and yield water-soluble and biocompatible fibrillar nanoplatforms for gene, drug and radionuclide delivery in vivo. Transmission electron microscopy of fCNC reveals a length of 162.4 ± 16.3 nm, diameter of 11.2 ± 1.52 nm and aspect ratio of 16.4 ± 1.94 per particle (mean ± SEM) and is confirmed using atomic force microscopy. Size exclusion chromatography of macromolecular fCNC describes a fibrillar molecular behavior as evidenced by retention times typical of late eluting small molecules and functionalized carbon nanotubes. In vivo, greater than 50% of intravenously injected radiolabeled fCNC is excreted in the urine within 1 h post administration and is consistent with the pharmacological profile observed for other rigid, high aspect ratio macromolecules. Tissue distribution of fCNC shows accumulation in kidneys, liver, and spleen (14.6 ± 6.0; 6.1 ± 2.6; and 7.7 ± 1.4% of the injected activity per gram of tissue, respectively) at 72 h post-administration. Confocal fluorescence microscopy reveals cell-specific accumulation in these target tissue sinks. In summary, our findings suggest that functionalized nanocellulose can be used as a potential drug delivery platform for the kidneys.


Asunto(s)
Celulosa/administración & dosificación , Nanopartículas/administración & dosificación , Nanopartículas/química , Animales , Celulosa/farmacocinética , Celulosa/toxicidad , Sistemas de Liberación de Medicamentos/instrumentación , Femenino , Ratones , Ratones Endogámicos C57BL , Microscopía de Fuerza Atómica , Nanopartículas/toxicidad , Tamaño de la Partícula , Distribución Tisular
13.
Clin Cancer Res ; 27(2): 532-541, 2021 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-32958698

RESUMEN

PURPOSE: Many cancer treatments suffer from dose-limiting toxicities to vital organs due to poor therapeutic indices. To overcome these challenges we developed a novel multimerization platform that rapidly removes tumor-targeting proteins from the blood to substantially improve therapeutic index. EXPERIMENTAL DESIGN: The platform was designed as a fusion of a self-assembling and disassembling (SADA) domain to a tandem single-chain bispecific antibody (BsAb, anti-ganglioside GD2 × anti-DOTA). SADA-BsAbs were assessed with multiple in vivo tumor models using two-step pretargeted radioimmunotherapy (PRIT) to evaluate tumor uptake, dosimetry, and antitumor responses. RESULTS: SADA-BsAbs self-assembled into stable tetramers (220 kDa), but could also disassemble into dimers or monomers (55 kDa) that rapidly cleared via renal filtration and substantially reduced immunogenicity in mice. When used with rapidly clearing DOTA-caged PET isotopes, SADA-BsAbs demonstrated accurate tumor localization, dosimetry, and improved imaging contrast by PET/CT. When combined with therapeutic isotopes, two-step SADA-PRIT safely delivered massive doses of alpha-emitting (225Ac, 1.48 MBq/kg) or beta-emitting (177Lu, 6,660 MBq/kg) S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA) payloads to tumors, ablating them without any short-term or long-term toxicities to the bone marrow, kidneys, or liver. CONCLUSIONS: The SADA-BsAb platform safely delivered large doses of radioisotopes to tumors and demonstrated no toxicities to the bone marrow, kidneys, or liver. Because of its modularity, SADA-BsAbs can be easily adapted to most tumor antigens, tumor types, or drug delivery approaches to improve therapeutic index and maximize the delivered dose.See related commentary by Capala and Kunos, p. 377.


Asunto(s)
Neoplasias , Radioinmunoterapia , Animales , Humanos , Ratones , Ratones Desnudos , Terapia Molecular Dirigida , Neoplasias/radioterapia , Tomografía Computarizada por Tomografía de Emisión de Positrones , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Theranostics ; 10(25): 11359-11375, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33052220

RESUMEN

This is the initial report of an α-based pre-targeted radioimmunotherapy (PRIT) using 225Ac and its theranostic pair, 111In. We call our novel tumor-targeting DOTA-hapten PRIT system "proteus-DOTA" or "Pr." Herein we report the first results of radiochemistry development, radiopharmacology, and stoichiometry of tumor antigen binding, including the role of specific activity, anti-tumor efficacy, and normal tissue toxicity with the Pr-PRIT approach (as α-DOTA-PRIT). A series of α-DOTA-PRIT therapy studies were performed in three solid human cancer xenograft models of colorectal cancer (GPA33), breast cancer (HER2), and neuroblastoma (GD2), including evaluation of chronic toxicity at ~20 weeks of select survivors. Methods: Preliminary biodistribution experiments in SW1222 tumor-bearing mice revealed that 225Ac could not be efficiently pretargeted with current DOTA-Bn hapten utilized for 177Lu or 90Y, leading to poor tumor uptake in vivo. Therefore, we synthesized Pr consisting of an empty DOTA-chelate for 225Ac, tethered via a short polyethylene glycol linker to a lutetium-complexed DOTA for picomolar anti-DOTA chelate single-chain variable fragment (scFv) binding. Pr was radiolabeled with 225Ac and its imaging surrogate, 111In. In vitro studies verified anti-DOTA scFv recognition of [225Ac]Pr, and in vivo biodistribution and clearance studies were performed to evaluate hapten suitability and in vivo targeting efficiency. Results: Intravenously (i.v.) administered 225Ac- or 111In-radiolabeled Pr in mice showed rapid renal clearance and minimal normal tissue retention. In vivo pretargeting studies show high tumor accumulation of Pr (16.71 ± 5.11 %IA/g or 13.19 ± 3.88 %IA/g at 24 h p.i. for [225Ac]Pr and [111In]Pr, respectively) and relatively low uptake in normal tissues (all average ≤ 1.4 %IA/g at 24 h p.i.). Maximum tolerated dose (MTD) was not reached for either [225Ac]Pr alone or pretargeted [225Ac]Pr at administered activities up to 296 kBq/mouse. Single-cycle treatment consisting of α-DOTA-PRIT with either huA33-C825 bispecific anti-tumor/anti-DOTA-hapten antibody (BsAb), anti-HER2-C825 BsAb, or hu3F8-C825 BsAb for targeting GPA33, HER2, or GD2, respectively, was highly effective. In the GPA33 model, no complete responses (CRs) were observed but prolonged overall survival of treated animals was 42 d for α-DOTA-PRIT vs. 25 d for [225Ac]Pr only (P < 0.0001); for GD2, CRs (7/7, 100%) and histologic cures (4/7, 57%); and for HER2, CRs (7/19, 37%) and histologic cures (10/19, 56%) with no acute or chronic toxicity. Conclusions: [225Ac]Pr and its imaging biomarker [111In]Pr demonstrate optimal radiopharmacologic behavior for theranostic applications of α-DOTA-PRIT. For this initial evaluation of efficacy and toxicity, single-cycle treatment regimens were performed in all three systems. Histologic toxicity was not observed, so MTD was not observed. Prolonged overall survival, CRs, and histologic cures were observed in treated animals. In comparison to RIT with anti-tumor IgG antibodies, [225Ac]Pr has a much improved safety profile. Ultimately, these data will be used to guide clinical development of toxicity and efficacy studies of [225Ac]Pr, with the goal of delivering massive lethal doses of radiation to achieve a high probability of cure without toxicity.


Asunto(s)
Partículas alfa/uso terapéutico , Neoplasias/terapia , Radioinmunoterapia/métodos , Radiofármacos/administración & dosificación , Nanomedicina Teranóstica/métodos , Actinio/administración & dosificación , Actinio/farmacocinética , Animales , Línea Celular Tumoral , Relación Dosis-Respuesta en la Radiación , Femenino , Semivida , Compuestos Heterocíclicos con 1 Anillo/administración & dosificación , Compuestos Heterocíclicos con 1 Anillo/química , Compuestos Heterocíclicos con 1 Anillo/farmacocinética , Humanos , Radioisótopos de Indio/administración & dosificación , Radioisótopos de Indio/farmacocinética , Ratones , Nanopartículas/administración & dosificación , Nanopartículas/química , Neoplasias/diagnóstico , Neoplasias/inmunología , Neoplasias/patología , Radioinmunoterapia/efectos adversos , Radiofármacos/química , Radiofármacos/farmacocinética , Dosificación Radioterapéutica , Distribución Tisular , Pruebas de Toxicidad Crónica , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Nat Rev Drug Discov ; 19(11): 819, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32895501

RESUMEN

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

16.
Nat Rev Drug Discov ; 19(9): 589-608, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32728208

RESUMEN

Radiopharmaceutical therapy (RPT) is emerging as a safe and effective targeted approach to treating many types of cancer. In RPT, radiation is systemically or locally delivered using pharmaceuticals that either bind preferentially to cancer cells or accumulate by physiological mechanisms. Almost all radionuclides used in RPT emit photons that can be imaged, enabling non-invasive visualization of the biodistribution of the therapeutic agent. Compared with almost all other systemic cancer treatment options, RPT has shown efficacy with minimal toxicity. With the recent FDA approval of several RPT agents, the remarkable potential of this treatment is now being recognized. This Review covers the fundamental properties, clinical development and associated challenges of RPT.


Asunto(s)
Neoplasias/tratamiento farmacológico , Radiofármacos/farmacología , Radiofármacos/uso terapéutico , Animales , Aprobación de Drogas/métodos , Humanos , Distribución Tisular/fisiología , Estados Unidos , United States Food and Drug Administration
17.
Proc Natl Acad Sci U S A ; 117(26): 15172-15181, 2020 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-32532924

RESUMEN

Hu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate-specific enzyme human kallikrein-related peptidase 2 (hK2; KLK2). In multiple rodent models, Actinium-225-labeled hu11B6-IgG1 ([225Ac]hu11B6-IgG1) has shown promising treatment efficacy. In the present study, we investigated options to enhance and optimize [225Ac]hu11B6 treatment. First, we evaluated the possibility of exploiting IgG3, the IgG subclass with superior activation of complement and ability to mediate FC-γ-receptor binding, for immunotherapeutically enhanced hK2 targeted α-radioimmunotherapy. Second, we compared the therapeutic efficacy of a single high activity vs. fractionated activity. Finally, we used RNA sequencing to analyze the genomic signatures of prostate cancer that progressed after targeted α-therapy. [225Ac]hu11B6-IgG3 was a functionally enhanced alternative to [225Ac]hu11B6-IgG1 but offered no improvement of therapeutic efficacy. Progression-free survival was slightly increased with a single high activity compared to fractionated activity. Tumor-free animals succumbing after treatment revealed no evidence of treatment-associated toxicity. In addition to up-regulation of canonical aggressive prostate cancer genes, such as MMP7, ETV1, NTS, and SCHLAP1, we also noted a significant decrease in both KLK3 (prostate-specific antigen ) and FOLH1 (prostate-specific membrane antigen) but not in AR and KLK2, demonstrating efficacy of sequential [225Ac]hu11B6 in a mouse model.


Asunto(s)
Actinio/uso terapéutico , Inmunoconjugados/uso terapéutico , Antígeno Prostático Específico/inmunología , Neoplasias de la Próstata/terapia , Calicreínas de Tejido/metabolismo , Partículas alfa , Animales , Biomarcadores de Tumor , Humanos , Masculino , Ratones , Ratones Desnudos , Neoplasias Experimentales/terapia
18.
Biomaterials ; 241: 119858, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32120314

RESUMEN

Lutetium-177 (177Lu) radiolabeled ultrasmall (~6 nm dia.) fluorescent core-shell silica nanoparticles (Cornell prime dots or C' dots) were developed for improving efficacy of targeted radiotherapy in melanoma models. PEGylated C' dots were surface engineered to display 10-15 alpha melanocyte stimulating hormone (αMSH) cyclic peptide analogs for targeting the melanocortin-1 receptor (MC1-R) over-expressed on melanoma tumor cells. The 177Lu-DOTA-αMSH-PEG-C' dot product was radiochemically stable, biologically active, and exhibited high affinity cellular binding properties and internalization. Selective tumor uptake and favorable biodistribution properties were also demonstrated, in addition to bulk renal clearance, in syngeneic B16F10 and human M21 xenografted models. Prolonged survival was observed in the treated cohorts relative to controls. Dosimetric analysis showed no excessively high absorbed dose among normal organs. Correlative histopathology of ex vivo treated tumor specimens revealed expected necrotic changes; no acute pathologic findings were noted in the liver or kidneys. Collectively, these results demonstrated that 177Lu-DOTA-αMSH-PEG-C' dot targeted melanoma therapy overcame the unfavorable biological properties and dose-limiting toxicities associated with existing mono-molecular treatments. The unique and tunable surface chemistries of this targeted ultrasmall radiotherapeutic, coupled with its favorable pharmacokinetic properties, substantially improved treatment efficacy and demonstrated a clear survival benefit in melanoma models, which supports its further clinical translation.


Asunto(s)
Melanoma Experimental , Melanoma , Nanopartículas , Animales , Línea Celular Tumoral , Humanos , Melanoma/radioterapia , Dióxido de Silicio , Distribución Tisular , alfa-MSH/metabolismo
19.
Cancer Biother Radiopharm ; 35(6): 459-473, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32013538

RESUMEN

An α particle-emitting nanodrug that is a potent and specific antitumor agent and also prompts significant remodeling of local immunity in the tumor microenvironment (TME) has been developed and may impact the treatment of melanoma. Biocompatible ultrasmall fluorescent core-shell silica nanoparticles (C' dots, diameter ∼6.0 nm) have been engineered to target the melanocortin-1 receptor expressed on melanoma through α melanocyte-stimulating hormone peptides attached to the C' dot surface. Actinium-225 is also bound to the nanoparticle to deliver a densely ionizing dose of high-energy α particles to cancer. Nanodrug pharmacokinetic properties are optimal for targeted radionuclide therapy as they exhibit rapid blood clearance, tumor-specific accumulation, minimal off-target localization, and renal elimination. Potent and specific tumor control, arising from the α particles, was observed in a syngeneic animal model of melanoma. Surprisingly, the C' dot component of this drug initiates a favorable pseudopathogenic response in the TME generating distinct changes in the fractions of naive and activated CD8 T cells, Th1 and regulatory T cells, immature dendritic cells, monocytes, MΦ and M1 macrophages, and activated natural killer cells. Concomitant upregulation of the inflammatory cytokine genome and adaptive immune pathways each describes a macrophage-initiated pseudoresponse to a viral-shaped pathogen. This study suggests that therapeutic α-particle irradiation of melanoma using ultrasmall functionalized core-shell silica nanoparticles potently kills tumor cells, and at the same time initiates a distinct immune response in the TME.


Asunto(s)
Partículas alfa/uso terapéutico , Portadores de Fármacos/química , Melanoma Experimental/radioterapia , Radiofármacos/administración & dosificación , Neoplasias Cutáneas/radioterapia , Microambiente Tumoral/efectos de la radiación , Actinio/administración & dosificación , Actinio/farmacocinética , Animales , Línea Celular Tumoral/trasplante , Biología Computacional , Modelos Animales de Enfermedad , Relación Dosis-Respuesta en la Radiación , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Humanos , Inmunidad Celular/genética , Inmunidad Celular/efectos de la radiación , Masculino , Dosis Máxima Tolerada , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ratones , Terapia Molecular Dirigida/métodos , Nanopartículas/química , RNA-Seq , Radiofármacos/farmacocinética , Receptor de Melanocortina Tipo 1/antagonistas & inhibidores , Receptor de Melanocortina Tipo 1/metabolismo , Dióxido de Silicio/química , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Distribución Tisular , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología
20.
Clin Cancer Res ; 25(2): 881-891, 2019 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-30254080

RESUMEN

PURPOSE: The impact of androgen receptor (AR) activity in breast cancer biology is unclear. We characterized and tested a novel therapy to an AR-governed target in breast cancer.Experimental Design: We evaluated the expression of prototypical AR gene products human kallikrein 2 (hK2) and PSA in breast cancer models. We screened 13 well-characterized breast cancer cell lines for hK2 and PSA production upon in vitro hormone stimulation by testosterone [dihydrotestosterone (DHT)]. AR-positive lines were further evaluated by exposure to estrogen (17ß-Estradiol) and the synthetic progestin D-Norgestrel. We then evaluated an anti-hK2-targeted radiotherapy platform (hu11B6), labeled with alpha (α)-particle emitting Actinium-225, to specifically treat AR-expressing breast cancer xenografts under hormone stimulation. RESULTS: D-Norgestrel and DHT activated the AR pathway, while 17ß-Estradiol did not. Competitive binding for AR protein showed similar affinity between DHT and D-Norgestrel, indicating direct AR-ligand interaction. In vivo production of hK2 was sufficient to achieve site-specific delivery of therapeutic radionuclide to tumor tissue at >20-fold over background muscle uptake; effecting long-term local tumor control. CONCLUSIONS: [225Ac]hu11B6 targeted radiotherapy was potentiated by DHT and by D-Norgestrel in murine xenograft models of breast cancer. AR activity in breast cancer correlates with kallikrein-related peptidase-2 and can be activated by D-Norgestrel, a common contraceptive, and AR induction can be harnessed for hK2-targeted breast cancer α-emitter radiotherapy.


Asunto(s)
Partículas alfa/uso terapéutico , Neoplasias de la Mama/metabolismo , Inmunoconjugados/administración & dosificación , Receptores Androgénicos/metabolismo , Transducción de Señal , Animales , Biomarcadores de Tumor , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Línea Celular Tumoral , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Femenino , Hexoquinasa/antagonistas & inhibidores , Humanos , Inmunoconjugados/farmacocinética , Ratones , Terapia Molecular Dirigida , Radioinmunoterapia , Radiometría , Transducción de Señal/efectos de los fármacos , Transducción de Señal/efectos de la radiación , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto
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