Biomedical subjects

Sven-Erik Strand

Publications and source records attributed to Sven-Erik Strand.

At least 19 recordsLinked to original sources

PubMed2005

Blood pharmacokinetics of various monoclonal antibodies labeled with a new trifunctional chelating reagent for simultaneous conjugation with 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid and biotin before radiolabeling.

PURPOSE: Knowledge of the blood pharmacokinetics of monoclonal antibodies is crucial in deciding the optimal time for starting the administration of a "clearing agent" or using a "clearing device." The primary purpose was to investigate whether the pharmacokinetics of various antibodies labeled with the same chelator and (111)In differed significantly after i.v. injection in immunocompetent rats. A new trifunctional chelator called "1033" containing a biotin and a radiometal chelation moiety is introduced, making it possible to use only one conjugation procedure for the antibody. EXPERIMENTAL DESIGN: Sixty-five non-tumor-bearing rats were included and divided into four groups (I-IV). The blood pharmacokinetics was investigated for rituximab, BR96, and trastuzumab labeled with 1033 and (111)In (I-III). The whole-body activity and activity uptake in muscle, liver, and kidney, which might explain differences in the early pharmacokinetics in blood, were also measured. hMN14 labeled with another chelator [1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)], but with the same radionuclide ((111)In-biotin-DOTA-hMN14), was studied (IV). The blood pharmacokinetics from another 15 tumor-bearing rats was compared with those of non-tumor-bearing rats (III) by injection of (111)In-1033-BR96. RESULTS: No statistical difference was detected between the groups regarding the blood pharmacokinetics of rituximab, BR96, or trastuzumab. The pharmacokinetics and biodistribution of (111)In-biotin-DOTA-hMN14 exhibited a clear difference compared with others. There were no significant differences in the blood pharmacokinetics of (111)In-1033-BR96 between tumor-bearing rats and non-tumor-bearing rats. CONCLUSIONS: Different antibodies labeled with the trifunctional chelator 1033 and (111)In did not exhibit different blood pharmacokinetics, which means that the pharmacokinetics could be predicted irrespective of the IgG1 antibody chosen. A small tumor burden did not change the pharmacokinetics of the radioimmunoconjugates.

Animals↗

PubMed2005

Determining maximal tolerable dose of the monoclonal antibody BR96 labeled with 90Y or 177Lu in rats: establishment of a syngeneic tumor model to evaluate means to improve radioimmunotherapy.

PURPOSE: To evaluate therapeutic strategies, it is essential to use biological models reflecting important aspects of the clinical situation. The aim of the present study was to compare the maximal tolerable dose of the monoclonal antibody BR96 labeled with 90Y or 177Lu in immunocompetent rats. Maximal tolerable dose was defined as the highest activity that allows 100% of the animals to survive without clinical signs, such as infections, bleeding, or diarrhea, and with <20% loss in body weight. EXPERIMENTAL DESIGN: Increasing activity levels of BR96 labeled with 90Y or 177Lu were administered to groups of rats. Blood parameters, body weight, and general performance were monitored for 8 weeks. RESULTS: Two days postinjection, all groups had decreased leukocyte counts down to 5% to 15% of initial values. Initiation of recovery (at 14-21 days) showed a dose-response relationship. All groups, except the group given the highest activity of 90Y, had complete resolution in their leukopenia. The decrease in platelets was delayed to days 7 to 14 postinjection with a dose-dependent response regarding both severity of the nadir (10-40% of initial value) and the start of recovery. Animals in the groups given the highest activities of both 90Y and 177Lu exhibited skin infections on day 21. CONCLUSIONS: The results showed good reproducibility and dose-dependent toxicity for both radionuclides, indicating that the maximal tolerable dose for 177Lu-BR96 (1,000 MBq/kg) is 1.7 times that for 90Y-BR96 (600 MBq/kg) in rats. This model makes it feasible to evaluate strategies to escalate therapeutic doses to tumors without increasing normal tissue toxicity.

Animals↗

PubMed2005

Dose-fractionated radioimmunotherapy in non-Hodgkin's lymphoma using DOTA-conjugated, 90Y-radiolabeled, humanized anti-CD22 monoclonal antibody, epratuzumab.

PURPOSE: Fractionated radioimmunotherapy may improve therapeutic outcome by decreasing heterogeneity of the dose delivered to the tumor and by decreasing hematologic toxicity, thereby allowing an increased amount of radionuclide to be administered. Because humanized anti-CD22 epratuzumab can be given repeatedly, a single-center study was conducted to establish the feasibility, safety, optimal dosing, and preliminary efficacy of weekly administrations of 90Y-labeled 1,4,7,10-tetra-azacyclodecane-N,N',N'',N'''-tetraacetic acid-conjugated epratuzumab. EXPERIMENTAL DESIGN: Cohorts of three to six patients with B-cell lymphoma received 185 MBq/m2 [90Y]epratuzumab with unconjugated epratuzumab (total protein dose 1.5 mg/kg) once weekly for two to four infusions, with [(111)In]epratuzumab coadministered at first infusion for scintigraphic imaging and dosimetry. RESULTS: Sixteen patients received treatment without significant infusional reactions. The overall objective response rate was 62% (95% confidence interval, 39-86%) in both indolent (75%) and aggressive disease (50%). Complete responses (CR/CRu) occurred in 25% of patients and were durable (event-free survival, 14-41 months). Two patients receiving four infusions had hematologic dose-limiting toxicity. Serum epratuzumab levels increased with each weekly dose. Of 13 patients with tumor cell CD22 expression determined by flow cytometry, seven of eight with strongly positive results had objective responses, versus one of five with negative or weakly positive results (P = 0.032). CONCLUSIONS: Radioimmunotherapy with weekly 185 MBq/m2 [90Y]epratuzumab achieved a high objective response rate (62%) across lymphoma subtypes, including durable CRs. The findings that three weekly infusions (555 MBq/m2, total dose) can be administered safely with only minor toxicity, that antibody levels increased during treatment weeks, and that therapeutic response predominantly occurs in patients with unequivocal CD22 tumor expression provide guidance for future studies.

Adult↗

PubMed2005

Evaluation of methods for red marrow dosimetry based on patients undergoing radioimmunotherapy.

Red marrow dosimetry is essential during radioimmunotherapy and a reliable method is essential in order to find a measure correlated to the toxic effect observed. The aim of this study was to calculate the absorbed dose to red marrow with different methods for the same patients and to compare the results. Patients diagnosed with B-cell lymphoma were treated with (131)I-labelled monoclonal antibodies (LL2, anti-CD22). Blood samples were collected, scintillation camera images were taken and single probe measurements were carried out at different points in time after administration of the radiopharmaceutical. The absorbed dose to red marrow per unit activity administered was calculated using four varieties of the blood method and from activity quantification in the sacrum in the scintillation camera images. The absorbed dose to the total body per unit activity, sometimes used as a measure for determining the toxic effect in red marrow, was calculated from both the scintillation camera images and the single probe measurements. The results from the different methods of calculating the absorbed dose for the same patient and treatment were compared. The ratio of the maximum and the minimum absorbed dose to red marrow calculated using the four variations of the blood method and the sacrum imaging method for one and the same patient varied between 1.8 and 2.8. The correlation coefficients for all the possible combinations of the dosimetry methods, including total body measurements, varied from 0.51 to 0.99. The results show that the variability of the absorbed dose to the bone marrow is dependent on both method and patient.

Animals↗

PubMed2005

Internal microdosimetry for single cells in radioimmunotherapy of B-cell lymphoma.

Patients with B-cell lymphoma may have disease manifestations ranging in size from more than a 1000 cm3 down to the volume of a single cell. If targeted radionuclide therapy is to become a curative treatment, all individual tumor cells must also be eliminated. Given the vast differences in particle energy of different electron- emitting radionuclides, one questions whether the mean absorbed dose is a relevant parameter for use in single-cell dosimetry and whether it would not be more accurate to adopt a stochastic approach to dosimetry. Monte Carlo simulations were performed of energy deposition from 1000, 300, 100, or 10 electrons uniformly distributed in a sphere with a radius of 7.7 microm. The simulated electrons were monoenergetic (18 keV, 28 keV, 141 keV, or 935 keV). The absorbed dose per emitted electron, the absorbed fraction, the fraction of the cellular volume in which energy is deposited, and the dose-volume histograms were calculated. Absorbed fractions varied between 0.60 (18 keV) and 0.001 (935 keV), and the absorbed dose to the cell per electron emitted varied by a factor of 10, from 0.898 mGy (18 keV) to 0.096 mGy (935 keV). The specific energy varied between 0 and 46 mGy for the case showing the best uniformity (1000 18-keV electrons). The nonuniformity of the absorbed dose to a cell increases with increasing electron energy and decreases with the number of decays inside the studied volume. The wide distribution of energy deposition should be taken into account when analyzing and designing trials for targeted radionuclide therapy.

Antibodies, Monoclonal↗

PubMed2005

A novel platform for radioimmunotherapy: extracorporeal depletion of biotinylated and 90Y-labeled rituximab in patients with refractory B-cell lymphoma.

Radioimmunotherapy is limited by the absorbed dose to radiosensitive organs. Removal of circulating radiolabeled MAbs after tumor tissue has been optimally targeted and should permit the administration of higher radioactivity to patients, resulting in a higher absorbed tumor dose. A novel "extracorporeal affinity adsorption treatment" (ECAT) device (MitraDep)was tested, with which biotinylated and radiolabeled MAbs can be removed from the circulation by passing whole blood over a filter coated with avidin. The antibodies were simultaneously radiolabeled and biotinylated using a trifunctional moiety comprising DOTA and biotin. Eight patients--all but 1 of whom with aggressive or mantle cell B-cell lymphoma-- who had failed to respond to standard therapies received infusions of 250 mg/m(2) cold rituximab and 150 MBq (111)In-rituximab-biotin for immunoscintigraphy. A week later, the patients were treated with another 250 mg/m(2) rituximab followed by (111)In/-(90)Y-rituximab-biotin (11 or 15 (90)Y MBq/kg). ECAT was performed 48 hours later. All 8 patients receiving (111)In-rituximab-biotin showed tumor uptake. Seven patients received radioimmunotherapy and subsequent ECAT. The mean depletion of (90)Y-rituximab-biotin in whole blood after ECAT was 96%, in the whole body 49%, in the lungs 62%, and in the liver and kidneys 40%. No effects on patients' vital signs and no adverse effects on hematological or coagulation parameters was observed during the ECAT procedure. A dose-escalation study is initiated.

Adsorption↗

PubMed2005

Dosimetry calculations on a tissue level by using the MCNP4c2 Monte Carlo code.

OBJECTIVE: The aim of this study was to develop a MCNP4c2-code and to further refine the small-scale anatomy intestinal dosimetry model based on a EGS4-code developed by Jonsson et al.(1,2) METHOD: The small intestine was modeled as a hexagonal tube system and includes cross-dose contribution from activity in nearby intestine loops. The model includes villi (height, 500 microm), radiosensitive crypt cells (height, 150 microm), and an overlying mucus layer of thicknesses (5-200 microm). The developed intestinal model used in either of the two Monte Carlo codes make it possible to calculate S-values and subsequent mean absorbed dose to the radiation-sensitive crypt cells in the small intestinal wall by considering contributions from the self-dose and from the cross-dose from nearby intestinal loops. Results are given for monoenergetic electrons and photons and for full decay schemes of (99m)Tc, (111)In, (131)I, (67)Ga, (90)Y, and (211)At. RESULTS: Results show that the cross-dose from nearby intestinal loops is significant, and that the fraction of cumulated activity in the intestinal wall contents is important for accurate absorbed-dose estimation. CONCLUSION: It is evident from our study that previous Medical Internal Radiation Dose (MIRD) and International Conference on Radiological Protection (ICRP) models tend to overestimate the absorbed dose to the wall. Our work on the gastrointestinal tract model includes several noticeable refinements, as compared to the MIRD- and ICRP model, and the "onion shell" geometry can easily be transferred to similar geometrical dosimetry applications.

Astatine↗

PubMed2005

The LundADose method for planar image activity quantification and absorbed-dose assessment in radionuclide therapy.

A new method for absorbed-dose assessment in radionuclide therapy is presented in this paper. The method is based on activity quantification by the conjugate-view methodology, applied to serial whole-body, anterior-posterior, scintillation-camera scans. The quantification method is an extension of previous studies, and includes separate corrections for attenuation, scatter, and overlapping organs. Further development has now been undertaken to take into account the capabilities of new dual-head camera systems with a built-in X-ray tube for anatomical imaging. Furthermore, the modeling of time-activity data is included, and dosimetric calculations based on the formalism by the Medical Internal Radiation Dose (MIRD) committee. To streamline absorbed-dose assessments for a large number of patient studies, the programs for quantification, image registration, and absorbed-dose calculations have been embedded in an envelop program termed LundADose, where calculations, to a great extent, are performed automatically. Evaluation of the whole-body activity quantification is performed for patients undergoing radioimmunotherapy by monoclonal antibodies labeled with (111)In or (90)Y.

Cobalt Radioisotopes↗

PubMed2005

Evaluation of accuracy in activity calculations for the conjugate view method from Monte Carlo simulated scintillation camera images using experimental data in an anthropomorphic phantom.

UNLABELLED: Activity determination from scintillation camera images using the conjugate view method may be inaccurate because of variation in scattered radiation from adjacent organs and activity from overlapping tissues. The aim of this study was to simulate patient scintillation camera images and from these evaluate the accuracy of 2 correction methods. The contribution from overlapping tissue activity was also calculated for some organs. METHODS: Biokinetic data for (99m)Tc-sestamibi obtained in rats was used as input to simulate scintillation camera images with a voxel-based computer phantom using the Monte Carlo method. The organ activity was calculated using the conjugate view method with either the effective attenuation coefficient method or scatter correction using the triple-energy window (TEW) method combined with attenuation correction with a transmission factor image. Images were simulated with activity in organs one by one to evaluate the accuracy of the 2 correction methods and to evaluate the activity contribution from activity in adjacent or overlapping tissues. To allow comparison with the clinical situation, the total activity distribution from the animal study was used to simulate scintillation camera images at different points in time and the calculated activity was compared with both the input data and some patient data from the literature. RESULTS: The combination of scatter and attenuation correction gave the most accurate calculated activity, +/-10% of the true activity from the images with activity in one organ at a time. In the images similar to the clinical situation, the kidney activity was overestimated up to a factor of 34, mainly because of excretion of activity through the intestines. CONCLUSION: The scatter correction using the TEW method in combination with attenuation correction with the measured transmission factor resulted in the most accurate activity determination of the methods used. This study also shows that organ activity data calculated from scintillation camera images may be overestimated by >90% because of activity in overlapping tissues.

Animals↗

PubMed2004

Absorbed dose distribution in glioma tumors in rat brain after therapeutic intratumoral injection of 201Tl-chloride.

Studies on animals with gliomas inoculated in the brain and treated with intratumoral injections of 201Tl-chloride have previously shown very promising results, with a survival several weeks longer than controls. Total regression was found in some animals, and necrosis was found in all the 201Tl-treated brain tumors. This study was undertaken to estimate the absorbed dose and dose distribution to the tumor based on the localization and clearance properties obtained from images with two high-resolution imaging techniques; pinhole single photon emission computed tomography (SPECT) and beta-camera. The images from the beta-camera were used to calculate the absorbed dose rate, using an in-house-developed, voxel-based Monte Carlo program, based on the EGS4 package. To evaluate the effects of different beta-particle energies on the absorbed dose rate distribution, simulations of medium- and high-energy electrons were conducted. Dose-volume histograms from these simulations show that the energy absorption is very locally distributed for 201Tl and medium energy, whereas high-energy beta emitters show a broader dose-volume distribution. The calculated total absorbed dose of 2-8 Gy in the tumor seems to be relativity low when considering the therapeutic effect that was seen. Further investigations, to determine the cause of the high therapeutic efficacy, are needed.

Animals↗

PubMed2004

Evaluation of parameters influencing S values in mouse dosimetry.

UNLABELLED: Clinical radionuclide therapy studies are commonly preceded by studies with small animals. Reliable evaluation of therapeutic efficacy must be based on accurate dosimetry. This study was performed to evaluate the influence of the mass of organs, the shape of organs, and the distances between organs on S values for mice. METHODS: A voxel-based version of a geometric model of a mouse was developed for input in our Monte Carlo program based on EGS4. Simulations were made for each source organ separately to resolve the S values for each organ. For verification purposes, S values were calculated for spheres of different masses and compared with the S values in the MIRDOSE3.1 software and with the S values on the Radiation Dose Assessment Resource Web site. The variation in the mass of the organs was determined from dissected mice. The influence of the shape of an organ was investigated by successive elongation of a sphere into spheroids with a constant mass. The right kidney was moved in the phantom of the mouse to evaluate the effect of organ distances on S values. The absorbed fractions for the mouse model presented here were compared with the results from some previously published models. The radionuclides used were (90)Y, (131)I, (111)In, and (99m)Tc. RESULTS: The results showed that the organ mass for one animal can differ by up to 33% from the mean mass. If linear interpolation from S value tables is used to obtain an S value for the specific mass of an organ, then the S value can differ by up to 80% from its true value. The corresponding deviation obtained by scaling according to mass is 20%. The shape of an organ was found to be the least important parameter for the S value. The cross-absorbed S value is strongly dependent on the geometry and the emitted radiation. For example, a 9.2-mm movement of the kidney can cause the S value from the liver to the right kidney to decrease to 0.05% of its original value for (90)Y. CONCLUSION: We conclude that the mass and the shape of organs and their locations relative to each other have considerable effects on mouse dosimetry.

Algorithms↗

PubMed2003

Change in tumor-absorbed dose due to decrease in mass during fractionated radioimmunotherapy in lymphoma patients.

PURPOSE: In radionuclide therapy, cumulated activity and tumor volume/mass are the principal quantities necessary for the calculation of the absorbed dose to the tumor. When treating a fast-responding macroscopic tumor, there may be a decrease in its mass during therapy, and at any given uptake, this will result in an increase in the absorbed dose. The purpose of the present work is to demonstrate the limitations in current internal dosimetry protocols that assume a fixed tumor mass in lymphoma patients, using a fractionated radioimmunotherapy schedule and using a single infusion. EXPERIMENTAL DESIGN: Patients with B-cell lymphoma were treated with (90)Y-labeled epratuzumab (Immunomedics, Inc., Morris Plains, NJ) using a weekly dose-fractionation schedule for 2-4 weeks. They received either 185 MBq/m(2) (5 mCi/m(2)) in each infusion or, if they had a history of high-dose chemotherapy with stem cell rescue, 92.5 MBq/m(2) (2.5 mCi/m(2)) in each infusion. All patients received (111)In-labeled epratuzumab with the first infusion to verify tumor targeting and for dosimetry. The present report is based on three selected patients, in whom repeated assessments of tumor mass were possible. In two patients, (111)In-labeled epratuzumab was also coadministered with one of the subsequent treatments, i.e. during the second and third of two and three scheduled infusions. The tumor volume was determined from computer tomography images obtained before the first infusion and on different times after the infusion. An exponential equation was fitted to the decreasing mass of the tumor and implemented in the calculation of the absorbed dose. For comparison, the absorbed dose to the tumor was also calculated using the tumor volume determined from the baseline pretreatment computer tomography examination. RESULTS: The tumor volume for the patients changed rapidly. For one patient, the pretreatment volume was 19.5 ml, and for another patient, it was 840 ml. For these two patients, the ratio of tumor volume at the beginning of therapy compared with that after 8 days and 14 days of therapy was 0.7 and 0.8, respectively. This rapid decrease in volume and subsequent mass reduction result in an increase of mean absorbed dose to the tumor of as much as a factor of 1.75. CONCLUSIONS: At a given activity uptake, a decrease in tumor mass during therapy will significantly increase the calculated absorbed dose. Taking the change in tumor mass into account when calculating absorbed dose may improve the correlation between the mean absorbed dose to the tumor and the response to the therapy.

Antibodies, Monoclonal↗

PubMed2003

3D absorbed dose calculations based on SPECT: evaluation for 111-In/90-Y therapy using Monte Carlo simulations.

A general method is presented for patient-specific three-dimensional (3D) absorbed dose calculations based on quantitative SPECT activity measurements. The computational scheme includes a method for registration of the CT study to the SPECT image, and compensation for attenuation, scatter, and collimator-detector response including septal penetration, performed as part of an iterative reconstruction method. From SPECT images, the absorbed dose rate is calculated using an EGS4 Monte Carlo code, which converts the activity distribution to an absorbed dose rate distribution. Evaluation of the accuracy in the activity quantification and the absorbed dose calculation is based on realistic Monte Carlo simulated SPECT data of a voxel-computer phantom and (111)In and (90)Y. Septal penetration was not included in this study. The SPECT-based activity concentrations and absorbed dose distributions are compared to the actual values; the results imply that the corrections for attenuation and scatter yield results of high accuracy. The presented method includes compensation for most parameters deteriorating the quantitative image information. Inaccuracies are, however, introduced by the limited spatial resolution of the SPECT system, which are not fully compensated by the collimator-response correction. The proposed evaluation methodology may be used as a basis for future inter-comparison of different dosimetry calculation schemes.

Humans↗

PubMed2003

Biotinylation, pharmacokinetics, and extracorporeal adsorption of humanized MAb 111In-MN14 using an avidin-affinity column in rats.

UNLABELLED: Extracorporeal adsorption (ECAT) reduces toxicity in radiosensitive organs by removing excess of biotinylated and radiolabeled MAb from unseparated blood in an avidin-agarose column. AIM: To investigate the influence of biotinylation on pharmacokinetics and biodistribution of humanized MAb (111)In-MN14 and to validate the effect of subsequent ECAT on activity reduction in the whole body, in blood, and in various organs after i.v. administration of biotinylated (111)In-hMN14 in rats. METHODS: Humanized MAb MN14 recognizes the carcinoembryonic antigen. Ninety-three rats were used. (111)In-hMN14-DOTA was biotinylated using NHS-biotin or Sulfo-NHS-biotin enabling antibodies to be absorbed on the avidin-agarose column. Eight rats underwent ECAT, which implied that three blood volumes were passed through the column during 2.5 h. Whole body counts and blood activity were monitored. At dissections, organs of interest were removed and measured for activity-content. RESULTS: HPLC showed signs of fragmentation at a low ratio of NHS-biotin/mg of MAb. No fragmentation or aggregation was observed using sulfo-NHS-biotin. When ECAT started at 6 h p.i., whole body and blood activity were reduced by 64% and 98%, respectively. The uptake in organs sensitive to radiation was also reduced, varying between 39% for the liver and 84% for the lungs and bone marrow. CONCLUSIONS: (111)In-hMN14 can be safely biotinylated using sulfo-NHS-biotin without significantly affecting antigenicity and biodistribution of the antibody. ECAT based on avidin-biotin concept effectively removed biotinylated (111)In-hMN14 from blood circulation and reduced activity in radiosensitive organs.

Absorption↗

PubMed2003

Crypt cell dosimetry for 99Tcm-sestamibi in a new small intestinal dosimetry model.

The aim of the study was to calculate the absorbed dose to the crypt cells in the small intestine from (99)Tc(m)-sestamibi excreted through the intestinal tract. The absorbed dose was calculated taking into consideration the biodistribution of the radiopharmaceutical in the small intestinal wall and its contents, based on data gathered in rats. Absorbed dose calculations were performed using a new intestinal model in which S values for crypt cells are given both for the intestinal wall and for the intestinal contents as source organs. A maximum of 6% of the injected activity was found to be located in the intestinal wall at 30 minutes after injection and 13% in the intestinal contents at 2 h, resulting in an absorbed dose of 8.9 microGy/MBq to the crypt cells. Assuming the activity to be located only in the wall, we calculate an absorbed dose to the crypt cells 2.5 times higher than if all the activity is assumed to be present in the intestinal contents. Using the new intestinal dosimetry model, together with detailed biokinetic data for the radiopharmaceutical from animal studies, it is possible to calculate the absorbed dose to the crypt cells, which is not possible when using external imaging.

Animals↗

PubMed2002

Time dependence of the activity concentration ratio of red marrow to blood and implications for red marrow dosimetry.

BACKGROUND: The method for red marrow dosimetry in radioimmunotherapy, in the absence of specific activity uptake in red marrow, is based on the activity measured in the blood or plasma. The activity concentration ratio of red marrow to blood is then assumed to be constant. The aim of the current study was to determine whether this ratio varies with time after injection. METHODS: Measurements were carried out with both animals and patients.Tumor-bearing rats were intravenously injected with iodine-131-, iodine-125-, indium-111-, or rhenium-188-labeled BR96, a chimeric immunoglobulin G1 monoclonal antibody. (All were chelate-labeled, except for iodine-131, which was iodogen-labeled.) Measurements were made of the activity concentration in blood and bone marrow at different points in time after injection, and the ratio of activity concentration in red marrow and blood as a function of time postinjection (RMBLR[t)]) was calculated. For patients treated with iodine-131-labeled monoclonal antibody (LL2, Immunomedics Inc., Morris Plains, NJ; anti-CD22; immunoglobulin G2 isotype of mouse origin), blood samples were drawn and scintillation camera images taken at different times after injection. The red marrow activity concentration in the sacrum was determined by activity quantification from regions of interest. The activity concentration in blood was also measured. The RMBLR(t) was calculated based on these data. RESULTS: For both patients and rats, the RMBLR(t) was increased 72 hours after injection. Furthermore, it was found that the use of a constant RMBLR can lead to an over- or underestimation of the absorbed dose in bone marrow. CONCLUSIONS: These data demonstrate the difficulty in using fixed values of the activity concentration ratio of red marrow to blood for dosimetry.

Animals↗

PubMed2002

Single tumor cell uptake and dosimetry of technetium-99m Fab' or minute anti-CD22 in low-grade B-cell lymphoma.

BACKGROUND: A patient with follicular lymphoma was investigated with 0.5 mg Fab' or minute anti-CD22 labeled with 1100 MBq technetium-99m ((99m)Tc). A computed tomography scan performed a week later revealed regression. This unexpected response prompted an investigation of single cell dosimetry of low-energy electron emitters. METHODS: Another patient with low-grade, unclassifiable B-cell lymphoma with a low expression of CD22 was injected with (99m)Tc anti-CD22. Blood samples were drawn 30 minutes, 4 hours, and 24 hours after injection. Lymphoma cells (CD19+) and T cells (CD3+), which served as control cells, were separated using a flow cytometer. The radioactivity of the two cell populations was measured in an NaI(Tl) well-type detector. The mean uptake per cell and absorbed dose were calculated. The CD22 expression of the patient's cells and of a B-cell lymphoma cell line (Raji) were assessed by flow cytometry for the extrapolation of the absorbed dose from the patient's cells to a cell line with higher CD22 expression. RESULTS: The average number of (99m)Tc atoms per CD19+ and CD3+ cell 4 hours postinjection were 5.4 and 0.054, respectively. Depending on the assumed ratio between antibody and CD22 molecules (1:2 or 1:1), the CD22 expression on the patient's cells and Raji cells varied from 2800 to 5700 and from 37,000 to 74,000 per cell, respectively. The average absorbed dose per cell ranged from 4 x 10(-7) to 0.1 grays (Gy). CONCLUSIONS: It seems feasible to assess the mean single tumor cell uptake of (99m)Tc targeted by Fab' or minute anti-CD22 in a patient's lymphoma using sorted cell populations, thereby allowing single cell dosimetry. Extrapolation of the absorbed dose from (99m)Tc to cells with higher CD22 expression was made and under certain conditions absorbed doses of 0.1 Gy were obtained, indicating the potential relevance of low-energy electron emitters to therapy.

Antigens, CD↗

PubMed2002

Application of extracorporeal immunoadsorption to reduce circulating blood radioactivity after intraperitoneal administration of indium-111-HMFG1-biotin.

BACKGROUND: Extracorporeal immunoadsorption (ECAT) is a method of reducing activity in radiosensitive organs by removing excess monoclonal antibodies (MAbs) from the blood. Previously, the authors experimentally evaluated ECAT based on the avidin-biotin concept after intravenous administration of radioimmunoconjugates. The aim of the current study was to determine whether ECAT could be used to reduce activity after intraperitoneal (i.p.) administration of indium-111((111)In)-HMFG1-biotin in rats, and to compare the pharmacokinetics of (111)In-HMFG1 with or without attached biotin after i.p. injection. METHODS: HMFG1, a murine immunoglobulin G(1) MAb that recognizes an epitope on the polymorphic epithelial mucin (PEM) antigen, was labeled with (111)In and then biotinylated. ECAT was explored from unseparated blood using an avidin-agarose adsorption column. Thirty rats were used as controls and 13 underwent ECAT. The whole-body (WB), blood, and organ activity were monitored. RESULTS: The binding capacity of (111)In-HMFG1-biotin to avidin was high. Biotinylation did not enhance the excretion of HMFG1. When ECAT was employed, the WB and blood radioactivity were reduced by 35-40% (P < 0.05) and 75--86% (P < 0.01), respectively. After the completion of ECAT, the activity uptake in organs was significantly decreased. CONCLUSIONS: ECAT was successfully applied after i.p. injection of the (111)In-HMFG-biotin MAb to reduce the radioactivity in the WB, blood, and radiosensitive organs. Due to redistribution of the radiolabeled MAbs during and after the completion of ECAT, the adsorption may have been prolonged or repeated. Biotinylation did not significantly change the biodistribution of the (111)In-HMFG1 in rats after intraperitoneal injection.

Animals↗