RESUMO
[212Pb]VMT01 is a melanocortin 1 receptor (MC1R) targeted theranostic ligand in clinical development for alpha particle therapy for melanoma. 212Pb has an elementally matched gamma-emitting isotope 203Pb; thus, [203Pb]VMT01 can be used as an imaging surrogate for [212Pb]VMT01. [212Pb]VMT01 human serum stability studies have demonstrated retention of the 212Bi daughter within the chelator following beta emission of parent 212Pb. However, the subsequent alpha emission from the decay of 212Bi into 208Tl results in the generation of free 208Tl. Due to the 10.64-hour half-life of 212Pb, accumulation of free 208Tl in the injectate will occur. The goal of this work is to estimate the human dosimetry for [212Pb]VMT01 and the impact of free 208Tl in the injectate on human tissue absorbed doses. Human [212Pb]VMT01 tissue absorbed doses were estimated from murine [203Pb]VMT01 biodistribution data, and human biodistribution values for 201Tl chloride (a cardiac imaging agent) from published data were used to estimate the dosimetry of free 208Tl. Results indicate that the dose-limiting tissues for [212Pb]VMT01 are the red marrow and the kidneys, with estimated absorbed doses of 1.06 and 8.27 mGyRBE = 5/MBq. The estimated percent increase in absorbed doses from free 208Tl in the injectate is 0.03% and 0.09% to the red marrow and the kidneys, respectively. Absorbed doses from free 208Tl result in a percent increase of no more than 1.2% over [212Pb]VMT01 in any organ or tissue. This latter finding indicates that free 208Tl in the [212Pb]VMT01 injectate will not substantially impact estimated tissue absorbed doses in humans.
Assuntos
Melanoma , Receptor Tipo 1 de Melanocortina , Animais , Quelantes , Cloretos , Humanos , Chumbo , Ligantes , Camundongos , Radioisótopos de Tálio , Distribuição TecidualRESUMO
Rationale: Transformed MUC1 (tMUC1) is a cancer-associated antigen that is overexpressed in >90% of triple-negative breast cancers (TNBC), a highly metastatic and aggressive subtype of breast cancer. TAB004, a murine antibody targeting tMUC1, has shown efficacy for the targeted delivery of therapeutics to cancer cells. Our aim was to evaluate humanized TAB004 (hTAB004) as a potential theranostic for TNBC. Methods: The internalization of hTAB004 in tMUC1 expressing HCC70 cells was assessed via fluorescent microscopy. hTAB004 was DOTA-conjugated and radiolabeled with Indium-111 or Actinium-225 and tested for stability and tMUC1 binding (ELISA, flow cytometry). Lastly, in vivo biodistribution (SPECT-CT), dosimetry, and efficacy of hTAB004 were evaluated using a TNBC orthotopic mouse model. Results: hTAB004 was shown to bind and internalize into tMUC1-expressing cells. A production method of 225Ac-DOTA-hTAB004 (yield>97%, RCP>97% SA=5 kBq/µg) and 111In-DOTA-hTAB004 (yield>70%, RCP>99%, SA=884 kBq/µg) was developed. The labeled molecules retained their affinity to tMUC1 and were stable in formulation and mouse serum. In NSG female mice bearing orthotopic HCC70 xenografts, the in vivo tumor concentration of 111In-DOTA-hTAB004 was 65 ± 15 %ID/g (120 h post injection). A single 225Ac-DOTA-hTAB004 dose (18.5 kBq) caused a significant reduction in tumor volume (P<0.001, day 22) and increased survival compared to controls (P<0.007). The human dosimetry results were comparable to other clinically used agents. Conclusion: The results obtained with hTAB004 suggest that the 111In/225Ac-DOTA-hTAB004 combination has significant potential as a theranostic strategy in TNBC and merits further development toward clinical translation.
Assuntos
Actínio/química , Antineoplásicos Imunológicos/farmacologia , Radioisótopos de Índio/química , Mucina-1/metabolismo , Radioimunoterapia/métodos , Neoplasias de Mama Triplo Negativas/terapia , Actínio/farmacocinética , Animais , Antineoplásicos Imunológicos/farmacocinética , Linhagem Celular Tumoral , Feminino , Humanos , Radioisótopos de Índio/farmacocinética , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Mucina-1/química , Medicina de Precisão , Distribuição Tecidual , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder that is characterized by episodic yet cumulative heterotopic ossification (HO) in skeletal muscles, tendons, and ligaments over a patient's lifetime. FOP is caused by missense mutations in the type I bone morphogenetic protein (BMP) receptor ACVR1. We have determined that the formation of heterotopic bone in FOP requires activation of mutant ACVR1 by Activin A, in part by showing that prophylactic inhibition of Activin A blocks HO in a mouse model of FOP. Here we piece together a natural history of developing HO lesions in mouse FOP, and determine where in the continuum of HO Activin A is required, using imaging (T2-MRI, µCT, 18 F-NaF PET/CT, histology) coupled with pharmacologic inhibition of Activin A at different times during the progression of HO. First, we show that expansion of HO lesions comes about through growth and fusion of independent HO events. These events tend to arise within a neighborhood of existing lesions, indicating that already formed HO likely triggers the formation of new events. The process of heterotopic bone expansion appears to be dependent on Activin A because inhibition of this ligand suppresses the growth of nascent HO lesions and stops the emergence of new HO events. Therefore, our results reveal that Activin A is required at least up to the point when nascent HO lesions mineralize and further demonstrate the therapeutic utility of Activin A inhibition in FOP. These results provide evidence for a model where HO is triggered by inflammation but becomes "self-propagating" by a process that requires Activin A. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
Assuntos
Ativinas/metabolismo , Miosite Ossificante/patologia , Ossificação Heterotópica/patologia , Animais , Imageamento por Ressonância Magnética , Camundongos , Miosite Ossificante/diagnóstico por imagem , Ossificação Heterotópica/diagnóstico por imagem , Microtomografia por Raio-XRESUMO
Atrial fibrillation (AF) is often successfully treated by catheter ablation. Those cases of AF that do not readily succumb to ablation therapy would benefit from improved methods for mapping the complex spatial patterns of tissue activation that typify recalcitrant AF. To this end, the purpose of our study was to investigate the use of numerical deconvolution to improve the spatial resolution of activation maps provided by 2-D arrays of intra-cardiac recording electrodes. We simulated tissue activation patterns and their corresponding electric potential maps using a computational model of cardiac electrophysiology, and sampled the maps over a grid of locations to generate a mapping data set. Following cubic spline interpolation, followed by edge-extension and windowing, we deconvolved the data and compared the results to the model current density fields. We performed a similar analysis on voltage-sensitive dye maps obtained in isolated sheep hearts. For both the synthetic data and the voltage-sensitive dye maps, we found that deconvolution led to visually improved map resolution for arrays of 10×10 up to 30×30 electrodes placed within a few mm of the atrial surface when the activation patterns included 3-4 features that spanned the recording area. Root mean square error was also reduced by deconvolution. Deconvolution of arrays of intracardiac potentials, preceded by appropriate interpolation and edge processing, leads to potentially useful improvements in map resolution that may allow more effective assessment of the spatiotemporal dynamics of tissue excitation during AF.