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This paper reviews some aspects and recent developments in the use of antibodies to target radionuclides for tumor imaging and therapy. While radiolabeled antibodies have been considered for many years in this context, only a few have reached the level of routine clinical use. However, alternative radionuclides, with more appropriate physical properties, such as lutetium-177 or copper-67, as well as alpha-emitting radionuclides, including astatine-211, bismuth-213, actinium-225, and others are currently reviving hopes in cancer treatments, both in hematological diseases and solid tumors. At the same time, PET imaging, with short-lived radionuclides, such as gallium-68, fluorine-18 or copper-64, or long half-life ones, particularly iodine-124 and zirconium-89 now offers new perspectives in immuno-specific phenotype tumor imaging. New antibody analogues and pretargeting strategies have also considerably improved the performances of tumor immunotargeting and completely renewed the interest in these approaches for imaging and therapy by providing theranostics, companion diagnostics and news tools to make personalized medicine a reality.

Unlabelled: New multiple myeloma (MM) treatments--such as high-dose melphalan therapy plus autologous stem cell transplantation or regimens incorporating bortezomide, thalidomide, and lenalidomide--substantially increase the rate of complete response that is associated with longer patient survival. Thus, maintaining the complete response status by improving the minimal residual disease after induction therapy is a key goal for MM management. Here, we address the question of radioimmunotherapy efficacy in MM minimal residual disease treatment in mice with a low tumor burden. α-emitters are particularly well adapted to this approach because the short range of α-particles enables localized irradiation of tumor cells within the bone marrow and a cytotoxic effect on isolated cells due to the high LET (linear energy transfer) of α-particles. The CD138 antigen was used as a target because of its strong expression on myeloma cells in 100% of patients., Method: Intravenous injection of 10(6) 5T33 mouse myeloma cells into the Syngeneic mouse strain C57BL/KaLwRij resulted in a rapid invasion of the marrow and limb paralysis, as illustrated by bioluminescence imaging with luciferase-transfected 5T33 cells. Radioimmunotherapy was performed 10 d after 5T33 cell engraftment with an intravenous injection of an antimouse CD138 antibody radiolabeled with (213)Bi at activities of 1.85, 3.7, 7.4, and 11.1 MBq. A blood cell count was performed weekly to monitor hematologic toxicity. The levels of blood Flt3 ligand were also measured to evaluate the radioimmunotherapy-related myelotoxicity. Disease progression was monitored by titrating the monoclonal IgG2b antibody produced by 5T33 cells., Results: The groups treated with 3.7 and 7.4 MBq exhibited a median survival greater than 300 and 227 d, respectively, compared with 45.5 d in the control untreated group. The highest activity (11.1 MBq) showed short-term toxicity whereas the lowest activity (1.85 MBq) gave results similar to those of the controls. With activities of 3.7 and 7.4 MBq, mice exhibited a transient hematologic toxicity whereas only temporary and moderate myelotoxicity was observed with 7.4 MBq., Conclusion: This study demonstrates promising therapeutic efficacy of (213)Bi-labeled anti-mCD138 for the treatment of residual disease in the case of MM, with only moderate and transient toxicity.

Alpha-particles are of considerable growing interest for Targeted Alpha Therapy (TAT). TAT gains more attention as new targets, chemical labeling techniques and α-particle emitters are developed but translation of TAT into the clinic has been slow, in part because of the limited availability and the short physical half-lives of some of the available α-particle emitters. This article is an up-to-date overview of the literature concerning α-emitters used for TAT of cancer. It briefly describes the nuclear characteristics, the production parameters (targets, extraction and purification), the complexation properties of these radionuclides to chelates and biological vectors and finally draws-upon the preclinical and clinical studies that have been performed over the past two decades. Radiobiology and dosimetry aspects are also presented in this paper.

Purpose: We investigated influences of pretargeting variables, tumor location, and radionuclides in pretargeted radioimmunotherapy (PRIT) as well as estimated tumor absorbed doses., Methods: LS-174T human colonic carcinoma cells expressing carcinoembryonic antigen (CEA) were inoculated in nude mice. Biodistribution of a bispecific anti-CEA x anti-hapten antibody, TF2, and of a TF2-pretargeted peptide was assessed and a multi-compartment pharmacokinetic model was devised. Tissue absorbed doses were calculated for (131)I, (177)Lu, (90)Y, (211)At, and (213)Bi using realistic specific activities., Results: Under conditions optimized for tumor imaging (10:1 TF2 to peptide molar ratio, interval time 15-24 h), tumor uptake reached ∼9 ID/g in subcutaneous tumors at 2 h with very low accretion in normal tissues (tumor to blood ratio >20:1 after 2 h). For a low dose of peptide (0.04 nmol), (211)At is predicted to deliver a high absorbed dose to tumors [41.5 Gy considering a relative biologic effect (RBE) of 5], kidneys being dose-limiting. (90)Y and (213)Bi would also deliver high absorbed doses to tumor (18.6 for (90)Y and 26.5 Gy for (213)Bi, taking RBE into account, for 0.1 nmol) and acceptable absorbed doses to kidneys. With hepatic metastases, a twofold higher tumor absorbed dose is expected. Owing to the low activities measured in blood, the bone marrow absorbed dose is expected to be without significant toxicity., Conclusion: Pretargeting achieves high tumor uptake and higher tumor to background ratios compared to direct RIT. Short-lived radionuclides are predicted to deliver high tumor absorbed doses especially (211)At, with kidneys being the dose-limiting organ. (177)Lu and (131)I should be considered for repeated injections.

A new high-energy and high-intensity cyclotron, ARRONAX, has been set into operation in 2010. ARRONAX can accelerate both negative ions (H- and D-) and positive ions (He++ and HH+). Protons can be accelerated from 30 MeV up to 70 MeV with a maximum beam intensity of 2 × 375 μAe whereas He++ can be accelerated at 68 MeV with a maximum beam current of 70 μAe. The main fields of application of ARRONAX are radionuclide production for nuclear medicine and irradiation of inert or living materials for radiolysis and radiobiology studies. A large part of the beam time will be used to produce radionuclides for targeted radionuclide therapy (copper-67, scandium-47 and astatine-211) as well as for PET imaging (scandium-44, copper-64, strontium-82 for rubidium-82 generators and germanium-68 for gallium-68 generators). Since the beginning of the project a particular interest has been devoted to alpha-radionuclide therapy using complex ligands like antibodies and astatine-211 has been selected as a radionuclide of choice for such type of applications. Associated with appropriate carriers, all these radionuclides will respond to a maximum of unmet clinical needs.

Purpose: This study was aimed at establishing a list of radionuclides of interest for nuclear medicine that can be produced in a high-intensity and high-energy cyclotron., Methods: We have considered both therapeutic and positron emission tomography radionuclides that can be produced using a high-energy and a high-intensity cyclotron such as ARRONAX, which will be operating in Nantes (France) by the end of 2008. Novel radionuclides or radionuclides of current limited availability have been selected according to the following criteria: emission of positrons, low-energy beta or alpha particles, stable or short half-life daughters, half-life between 3 h and 10 days or generator-produced, favourable dosimetry, production from stable isotopes with reasonable cross sections., Results: Three radionuclides appear well suited to targeted radionuclide therapy using beta ((67)Cu, (47)Sc) or alpha ((211)At) particles. Positron emitters allowing dosimetry studies prior to radionuclide therapy ((64)Cu, (124)I, (44)Sc), or that can be generator-produced ((82)Rb, (68)Ga) or providing the opportunity of a new imaging modality ((44)Sc) are considered to have a great interest at short term whereas (86)Y, (52)Fe, (55)Co, (76)Br or (89)Zr are considered to have a potential interest at middle term., Conclusions: Several radionuclides not currently used in routine nuclear medicine or not available in sufficient amount for clinical research have been selected for future production. High-energy, high-intensity cyclotrons are necessary to produce some of the selected radionuclides and make possible future clinical developments in nuclear medicine. Associated with appropriate carriers, these radionuclides will respond to a maximum of unmet clinical needs.

The authors discuss the clinical effectiveness of pretargeted radioimmunotherapy (PRIT) than the traditional radioimmunotherapy (RIT) for tumour treatments. They state the two approaches practiced in medical studies including one which uses biotin and avidin interaction, and another on hapten and bispecific antibody (BsMAb). They mention that the studies used radionuclides and antibodies to compare the PRIT and RIT. They add that PRIT is efficient for immuno-positron emission tomography (PET).

During the past two decades, considerable research has been devoted to radionuclide therapy using radiolabelled monoclonal antibodies and receptor binding agents. Conventional Radioimmunotherapy (RIT) is now an established and important tool in the treatment of hematologic malignancies such as Non-Hodgkin lymphoma. For solid malignancies, the efficacy of RIT has not been as successful due to lower radiosensitivity, difficult penetration of the antibody into the tumor and potential excessive radiation to normal tissues. Innovative approaches have been developed in order to enhance tumor absorbed dose while limiting toxicity to overcome the different limitations due to the tumor and host characteristics. Pretargeting techniques (pRIT) are a promising approach that consists of decoupling the delivery of a tumor monoclonal antibody (mAb) from the delivery of the radionuclide. This results in a much higher tumor-to-normal tissue ratio and is favorable for therapy as well and imaging. This includes various strategies based on avidin/streptavidin-biotin, DNAcomplementary DNA and bispecific antibody-hapten bindings. PRIT continuously evolves with the investigation of new molecular constructs and the development of radiochemistry. Pharmacokinetics improve dosimetry depending on the radionuclides used (alpha, beta and Auger emitters) with prediction of tumor response and host toxicities. New constructs such as the Dock and Lock technology allow production of a variety of mABs directed against tumorassociated antigens. Survival benefit has already been shown in medullary thyroid carcinoma. Improvement in delivery of radioactivity to tumors with these pretargeting procedures associated with reduced hematologic toxicity will become the next generation of RIT. The following review addresses actual technical and clinical considerations and future development of pRIT. [ABSTRACT FROM AUTHOR]

Small animal dosimetry serves as an important link in establishing a relationship between absorbed dose and biological effect during preclinical targeted radionuclide therapy. Dosimetric approaches reported to date are based on models aiming at representing the animals used during preclinical experiments. However, anatomical variations between models may generate differences in the dosimetric results. Our goal was to assess the impact of the mouse model on the absorbed dose per cumulated activity (S-value, in gray per becquerel-seconds). Two datasets were considered. The first one was developed in our laboratory and is a voxel-based model of a 30-g female nude mouse. Images were segmented manually to identify more than 30 organs and suborgans. The second dataset originates from the DIGIMOUSE project. In that model, a 28-g normal male nude mouse was used to generate the segmented structures of nine regions in the head and 12 major organs. A software developed in our laboratory allowed us to read each three-dimensional mouse atlas slice by slice, to crop the mouse volume to remove background air voxels, and to write the geometry description as an input file for the Monte Carlo code MCNPX using "repeated structure representation." A linear interpolation scales the voxel size as a function of the total body mass. The comparison of various voxel-based mouse dosimetric models shows that even when scaled to the same total-body mass, models from different mouse breed or gender demonstrate very different organ masses, volumes, and, therefore, S-values. Computation of the S-values for preclinical studies depends strongly on the definition of the mouse model. Our computational model is a step in the direction of a more realistic description of the geometry in preclinical dosimetry. [ABSTRACT FROM AUTHOR]

Radioimmunotherapy (RIT) has been proven effective in the treatment of radiosensitive non-Hodgkin lymphoma but, for radioresistant solid tumors, new approaches are necessary to improve the clinical effectiveness. A real improvement has been the introduction of the pretargeting technology which appeared to be able to significantly increase tumor-to-normal organ uptake ratios.Another very promising approach consists in associating RIT with other treatment modalities. Finally the use of alpha particle-emitting radionuclides such as astatin-211 or bismuth-213 (alpha-RIT) should allow to efficiently eradicate disseminated microscopic clusters of tumor cells or isolated tumor cells which fit well with the short path length of alpha particles. [ABSTRACT FROM AUTHOR]

A new method to label preformed liposomes with high activities of radiohalogenated compounds has been developed. It uses activated esters of simple synthetic molecules that may be readily halogenated, such as Bolton-Hunter reagent (BH), and arginine-containing liposomes. BH, in the form of an activated ester, crosses the liposome membrane to react with arginine inside the liposomes, as demonstrated by thin-layer chromatography and by the fact that saline-containing liposomes, or hydrolyzed BH or the water soluble sulfo-BH afforded only marginal encapsulation yields. Under optimized conditions, between 37 and 55°C, 62 ± 4% (mean ± SD) of radiolabeled BH were consistently encapsulated in the liposomes within 30 min. In molar amounts, this corresponds to a mean of 56 nmol of BH per µmol of lipids. Based on achievable specific activity, up to 2.8 GBq of iodine-131 could be entrapped per µmol of lipids. Leakage of radioactivity was very low, with less than 5% of the encapsulated activity released within 6 days at 4°C in phosphate-buffered saline and less than 50% within 24h in human serum at 37°C. The labeling stability, and the fact that both conventional and PEGylated liposomes can be readily labeled with high doses of radioactivity, will make this technique useful for in vivo targeting applications, such as tumor detection (using iodine-123 or iodine-124) or therapy (with iodine-131 or astatine-211). [ABSTRACT FROM AUTHOR]

Simple Summary: The prevalence of TEM-1 in the vasculature and the stroma of solid tumors and in malignant cells of sarcomas suggests that targeting TEM-1 could have therapeutic benefit. In this context, an anti-TEM-1 companion diagnostic may assist in the personalized medicine approach, whereby TEM-1 expression is exploited as a biomarker to select patients that would most benefit from a treatment directed toward the TEM-1 antigen. In our previous works, we have selected 1C1m-Fc, a fusion protein antibody, radiolabeled it with 177Lu and demonstrated that [177Lu]Lu-1C1m-Fc has interesting therapeutic performance. To define a suitable radiopharmaceutical companion for theranostic applications, 64Cu was chosen to radiolabel the fusion protein antibody. The aim of this work was thus to determine if [64Cu]Cu-1C1m-Fc can be considered for TEM-1 PET imaging and to predict the dosimetry of the [177Lu]Lu-1C1m-Fc companion therapy. 1C1m-Fc, a promising anti-TEM-1 DOTA conjugate, was labeled with 64Cu to target cancer cells for PET imaging and predicting the efficacy and safety of a previously studied [177Lu]Lu-1C1m-Fc companion therapy. DOTA-conjugated 1C1m-Fc was characterized by mass spectrometry, thin layer chromatography and immunoreactivity assessment. PET/CT and biodistribution studies were performed in human neuroblastoma xenografted mice. Absorbed doses were assessed from biodistribution results and extrapolated to 177Lu based on the [64Cu]Cu-1C1m-Fc data. The immunoreactivity was ≥ 70% after 48 h of incubation in serum, and the specificity of [64Cu]Cu-1C1m-Fc for the target was validated. High-resolution PET/CT images were obtained, with the best tumor-to-organ ratios reached at 24 or 48 h and correlated with results of the biodistribution study. Healthy organs receiving the highest doses were the liver, the kidneys and the uterus. [64Cu]Cu-1C1m-Fc could be of interest to give an indication of 177Lu dosimetry for parenchymal organs. In the uterus and the tumor, characterized by specific TEM-1 expression, the 177Lu-extrapolated absorbed doses are overestimated because of the lack of later measurement time points. Nevertheless, 1C1m-Fc radiolabeled with 64Cu for imaging would appear as an interesting radionuclide companion for therapeutic application with [177Lu]Lu-1C1m-Fc. [ABSTRACT FROM AUTHOR]

In this article the author discusses the use of radiolabelled monoclonal antibodies for treating cancers such as non-Hodgkin's lymphoma and thyroid cancer. The author provides an overview on the use of alpha particle-emitting radionuclides for the treatment of residual disease. The author also notes that the clinical use of gemtuzumab ozogamicin is no longer accepted in Europe because of its side effects and poor efficacy.

The application of 211 At to targeted cancer therapy is currently hindered by the rapid deastatination that occurs in vivo . As the deastatination mechanism is unknown, we tackled this issue from the viewpoint of the intrinsic properties of At-involving chemical bonds. An apparent correlation has been evidenced between in vivo stability of 211 At-labeled compounds and the At−R (R = C, B) bond enthalpies obtained from relativistic quantum mechanical calculations. Furthermore, we highlight important differences in the nature of the At−C and At−B bonds of interest, e.g. the opposite signs of the effective astatine charges, which implies different stabilities with respect to the biological medium. Beyond their practical use for rationalizing the labeling protocols used for 211 At, the proposed computational approach can readily be used to investigate bioactive molecules labeled with other heavy radionuclides. [ABSTRACT FROM AUTHOR]

Targeted PEGylated liposomes could increase the amount of drugs or radionuclides delivered to tumor cells. They show favorable stability and pharmacokinetics, but steric hindrance of the PEG chains can block the binding of the targeting moiety. Here, specific interactions between an antihapten antibody (clone 734, specific for the DTPA-indium complex) and DTPA-indiumtagged liposomes were characterized by surface plasmon resonance (SPR). Non-PEGylated liposomes fused on CM5 chips whereas PEGylated liposomes did not. By contrast, both PEGylated and non-PEGylated liposomes attached to L1 chips without fusion. SPR binding kinetics showed that, in the absence of PEG, the antibody binds the hapten at the surface of lipid bilayers with the affinity of the soluble hapten. The incorporation of PEGylated lipids hinders antibody binding to extents depending on PEGylated lipid fraction and PEG molecular weight. SPR on immobilized liposomes thus appears as a useful technique to optimize formulations of liposomes for targeted therapy. [ABSTRACT FROM AUTHOR]