ABSTRACT
Intrapatient variation in the biodistribution of the chimeric monoclonal antibody cT84.66 was assessed in 19 patients having a variety of carcinoembryonic antigen (CEA) positive tumors. The two studies, including whole-body imaging and blood and urine specimen collections, were conducted within 14 days of each other using (111)In-cT84.66 at a fixed total protein dose of 5 mg per patient per study. An initial pretherapy infusion of (111)In-cT84.66 was administered followed by a therapy coinfusion of (111)In-ct84.66 and 90Y-cT84.66 A closed five-compartment model was used to integrate source organ activity curves as residence time inputs into the MIRDOSE3 program. Normal organ absorbed doses were estimated for 90Y-cT84.66, the corresponding radiotherapeutic agent. For the two (111)In-cT84.66 biodistributions, all data were modeled with a R2 value of between 0.72 and 1.00 with the exception of the urine data taken during therapy. This was due to the need of diethylenetriaminepentaacetic acid during the therapy phase because of the possibility that yttrium might escape from the chelator attached to the antibody. With the assurance that the biodistributions were reproducible, we were able to estimate the 90Y-cT84.66 absorbed doses on a per-patient basis. Concordance coefficients showing the agreement between the imaging and therapy phase dose estimates were between the 0.60 and 0.99 levels for liver, spleen, red marrow, total body, and other organ systems. Median results were: 27, 17, and 2.7 rad/mCi of 90Y-cT84.66 for liver, spleen, and red marrow, respectively. Because of decreases in platelets and white cells as the amount of 90Y was increased, dose-limiting toxicity was found at 22 mCi/m2. We conclude that patient biodistributions were consistent over time to 14 days so as to allow absorbed dose estimation in a radioimmunotherapy trial involving the cT84.66 anti-CEA antibody.
Subject(s)
Radioimmunotherapy/methods , Radiotherapy Planning, Computer-Assisted , Yttrium Radioisotopes/therapeutic use , Adult , Aged , Female , Humans , Indium Radioisotopes/blood , Indium Radioisotopes/urine , Male , Middle Aged , Reproducibility of Results , Time Factors , Tissue Distribution , Yttrium Radioisotopes/blood , Yttrium Radioisotopes/urineABSTRACT
UNLABELLED: Chimeric T84.66 (cT84.66) is a high-affinity (1.16x10(11) M(-1)) IgG1 monoclonal antibody against carcinoembryonic antigen (CEA). The purpose of this pilot trial was to evaluate the tumor-targeting properties, biodistribution, pharmacokinetics and immunogenicity of 111In-labeled cT84.66 as a function of administered antibody protein dose. METHODS: Patients with CEA-producing colorectal cancers with localized disease or limited metastatic disease who were scheduled to undergo definitive surgical resection were each administered a single intravenous dose of 5 mg of isothiocyanatobenzyl diethylenetriaminepentaacetic acid-cT84.66, labeled with 5 mCi of 111In. Before receiving the radiolabeled antibody, patients received unlabeled diethylenetriaminepentaacetic acid-cT84.66. The amount of unlabeled antibody was 0, 20 or 100 mg, with five patients at each level. Serial blood samples, 24-hr urine collections and nuclear images were collected until 7 days postinfusion. Human antichimeric antibody response was assessed up to 6 mo postinfusion. RESULTS: Imaging of at least one known tumor site was performed in all 15 patients. Fifty-two lesions were analyzed, with an imaging sensitivity rate of 50.0% and a positive predictive value of 76.9%. The antibody detected tumors that were not detected by conventional means in three patients, resulting in a modification of surgical management. Interpatient variations in serum clearance rates were observed and were secondary to differences in clearance and metabolic rates of antibody and antibody:antigen complexes by the liver. Antibody uptake in primary tumors, metastatic sites and regional metastatic lymph nodes ranged from 0.4% to 134% injected dose/kg, resulting in estimated 90Y-cT84.66 radiation doses ranging from 0.3 to 193 cGy/mCi. Thirteen patients were evaluated 1-6 mo after infusion for human antichimeric antibody, and none developed a response. No major differences in tumor imaging, tumor uptake, pharmacokinetics or organ biodistribution were observed with increasing protein doses, although a trend toward increasing blood uptake and decreasing liver uptake was observed with increasing protein dose. CONCLUSION: Chimeric T84.66 demonstrated tumor targeting comparable to other radiolabeled intact anti-CEA monoclonal antibodies. Its immunogenicity after single administration was lower than murine monoclonal antibodies. These properties make 111In-cT84.66, or a lower molecular weight derivative, attractive for further evaluation as an imaging agent. Yttrium-90 dosimetry estimates predict potentially cytotoxic radiation doses to select tumor sites, which makes 90Y-cT84.66 also appropriate for further evaluation in Phase I radioimmunotherapy trials. Although clinically important changes in biodistribution, pharmacokinetics and tumor targeting with increasing protein doses of 111In-cT84.66 were not demonstrated, the results do suggest that antibody clearance from the blood is driven by hepatic uptake and metabolism, with more rapid blood clearance seen in patients with liver metastases. These patients with rapid clearance and potentially unfavorable biodistribution for imaging and therapy may, therefore, be a more appropriate subset in which to evaluate the role of administering higher protein doses. This underscores the need to further identify, characterize and understand those factors that influence the biodistribution and clearance of radiolabeled anti-CEA antibodies, to allow for better selection of patients for therapy and rational planning of radioimmunotherapy.
Subject(s)
Colorectal Neoplasms/radiotherapy , Colorectal Neoplasms/surgery , Indium Radioisotopes/therapeutic use , Adult , Aged , Animals , Antibodies, Monoclonal/adverse effects , Carcinoembryonic Antigen/immunology , Colorectal Neoplasms/diagnostic imaging , Colorectal Neoplasms/pathology , Female , Humans , Immunoglobulin G/adverse effects , Indium Radioisotopes/adverse effects , Indium Radioisotopes/pharmacokinetics , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/secondary , Lymphatic Metastasis , Male , Metabolic Clearance Rate , Mice , Middle Aged , Neoplasm Metastasis , Pilot Projects , Radiography , Radioimmunotherapy , Radionuclide Imaging , Radiopharmaceuticals/adverse effects , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/therapeutic use , Radiotherapy Dosage , Radiotherapy, Adjuvant , Sensitivity and Specificity , Tissue DistributionABSTRACT
Biodistributions of two radiometal chelate conjugates of the human/murine chimeric anticarcinoembryonic antigen monoclonal antibody cT84.66 were obtained in nude mice bearing LS174T human colorectal carcinoma xenografts. Derivatives of the macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) were covalently attached to the antibody by a stable amide linkage and by a maleimidocysteineamido side chain (MC-DOTA) that has been shown to be chemically labile at physiological temperature and pH. Biodistributions of both 111In and 90Y labels were obtained in these studies. At common biodistribution time points, it was found that the 111In label had greater uptake in the liver than 90Y for both conjugates. No significant differences were found with respect to bone uptake of 90Y using either chelate. Blood curves were generally lower at comparable time points for MC-DOTA, indicative of faster clearance as compared to DOTA. Tumor uptake was high for both conjugates (57-68% ID/g at 48 h), with a longer tumor residence time in the case of the DOTA conjugate, probably a result of its longer blood circulation times. We conclude that bone uptake of 90Y would be minimal if either DOTA or MC-DOTA were used as the bifunctional chelator. This would imply preference for these macrocyclic ligands if radiation doses to the bone marrow would be considered to be dominated by skeletal uptakes. Alternatively, if bone marrow radiation dose is dominated by circulating antibody, the chemically labile linker system employed by the MC-DOTA conjugate offers the advantage of enhanced blood clearance.
Subject(s)
Antibodies, Monoclonal/chemistry , Carcinoembryonic Antigen/immunology , Chelating Agents/pharmacokinetics , Heterocyclic Compounds, 1-Ring , Heterocyclic Compounds/pharmacokinetics , Maleimides/pharmacokinetics , Neoplasm Transplantation , Animals , Bone Marrow/metabolism , Bone and Bones/metabolism , Colorectal Neoplasms/metabolism , Drug Stability , Humans , Indium Radioisotopes/pharmacokinetics , Isotope Labeling , Mice , Mice, Nude , Tissue Distribution , Transplantation, Heterologous , Yttrium Radioisotopes/pharmacokineticsABSTRACT
OBJECTIVE: An approach for estimating organ residence times (tau) and their errors in patient internal emitter radiation dosage calculations has been determined. METHODS: Using a modeling algorithm and its associated parameters, chimeric anti-CEA monoclonal antibody (cT84.66) patient organ uptake data and residence times of source organ activity were calculated. Through the covariance matrix of the model's parameters and subsequent Monte Carlo simulations, errors in organ residence time (gamma tau) also were estimated RESULTS: These relative tau errors were found to be model-dependent; increasing as the number of organs being simultaneously modeled in a set of two patients being considered for 90Y-cT84.66 radioimmunotherapy. CONCLUSION: Use of modeling and Monte Carlo methods provide a general, direct procedure for calculating the degree of accuracy of activity integrals and other mathematical functions of kinetic variables.
Subject(s)
Radioimmunotherapy , Algorithms , Humans , Indium Radioisotopes/therapeutic use , Monte Carlo Method , Radiotherapy Dosage , Yttrium Radioisotopes/therapeutic useABSTRACT
UNLABELLED: Chimeric T84.66 (cT84.66) is a high-affinity (1.16 x 10[11] M[-1]) IgG1 monoclonal antibody (MAb) against carcinoembryonic antigen (CEA). This pilot trial evaluated the tumor-targeting properties, biodistribution, pharmacokinetics and immunogenicity of 111In-labeled cT84.66. METHODS: Patients with CEA-producing metastatic malignancies were administered a single intravenous dose of 5 mCi 111In-diethylenetriaminepentaacetic acid-cT84.66. Serial blood samples, 24-hr urine collections and nuclear images were collected up to 7 days postinfusion. Human antichimeric antibody response was assessed up to 6 mo postinfusion. RESULTS: Imaging of at least one known tumor site was observed in 14 of 15 (93%) patients. Seventy-four lesions were analyzed with an imaging sensitivity rate of 45.1% and a positive predictive value of 94.1%. In one patient, two additional bone metastases developed within 6 mo of antibody administration at sites initially felt to be falsely positive on scan. One patient developed a human antichimeric antibody response predominantly to the murine portion of the antibody. The antibody cleared serum with a median T(1/2alpha) of 6.53 hr and a T(1/2beta) of 90.87 hr. Interpatient variations in serum clearance rates were observed and were secondary to differences in clearance and metabolic rates of antibody-antigen complexes by the liver. One patient demonstrated very rapid clearance of antibody by the liver, which compromised antibody localization to the primary tumor. Antibody uptake in primary and metastatic tumors ranged from 0.5% to 10.5% injected dose/kg, resulting in estimated radiation doses ranging from 0.97 to 21.3 cGy/mCi 90Y. Antibody uptake in regional lymph nodes ranged from 1.3% to 377% injected dose/kg, resulting in estimated radiation doses ranging from 2.0 to 617 cGy/mCi 90Y. CONCLUSION: Chimeric T84.66 demonstrated tumor targeting that was comparable to that of other radiolabeled intact anti-CEA Mabs. Its immunogenicity after single administration was lower than murine Mabs. These properties make cT84.66 or a lower molecular weight derivative attractive for further evaluation as an imaging agent. These same properties also make it appropriate for future evaluation in Phase I therapy trials. Finally, a wide variation in the rate of antibody clearance was observed, with one patient demonstrating very slow clearance, resulting in the highest estimated marrow dose of the group, and one patient demonstrating unusually rapid clearance, resulting in poor antibody localization to tumor. Data from this study suggest that serum CEA levels, antibody-antigen complex clearance and, therefore, antibody clearance are influenced by both the production and clearance rates of CEA. This underscores the need to further identify, characterize and understand those factors that influence the biodistribution and clearance of radiolabeled anti-CEA antibodies to allow for better selection of patients for therapy and rational planning of radioimmunotherapy.
Subject(s)
Carcinoembryonic Antigen/immunology , Indium Radioisotopes/therapeutic use , Radioimmunodetection , Radioimmunotherapy , Adult , Aged , Animals , Female , Humans , Indium Radioisotopes/pharmacokinetics , Male , Mice , Middle Aged , Pilot Projects , Predictive Value of Tests , Recombinant Fusion Proteins/pharmacokinetics , Recombinant Fusion Proteins/therapeutic use , Sensitivity and Specificity , Tissue Distribution , Yttrium Radioisotopes/pharmacokinetics , Yttrium Radioisotopes/therapeutic useABSTRACT
UNLABELLED: The objective of this article was to model pharmacokinetic data from clinical diagnostic studies involving the 111In-labeled monoclonal antibody (MAb) chimeric T84.66, against carcinoembryonic antigen. Model-derived results based on the 111In-MAb blood, urine and digital imaging data were used to predict 90Y-MAb absorbed radiation doses and to guide treatment planning for future therapy trials. Fifteen patients with at least one carcinoembryonic antigen-positive lesion were evaluated. We report the kinetic parameter estimates and absorbed 111In-MAb dose and projected 90Y-MAb doses for each patient as well as describe our approach and rationale for modeling an extensive set of pharmacokinetic data. METHODS: The ADAPT II software package was used to create three- and five-compartment models of uptake against time in the patient population. The "best-fit" model was identified using ordinary least squares. Areas under the curve were calculated using the modeled curves and input into MIRDOSE3 to estimate absorbed radiation doses for each patient. RESULTS: A five-compartment model best described the liver, whole body, blood and urine data for a subcohort of nine patients with digital imaging data. A three-compartment model best described the blood and urine data for all 15 clinical patients accrued in the clinical trial. For the subcohort, the largest projected 90Y-MAb doses were delivered to the liver (mean, 24.78 rad/mCi; range, 15.02-37.07 rad/mCi), with red marrow estimates on the order of 3.32 rad/mCi (range, 1.24-5.55) of 90Y. Corresponding estimates for the 111In-MAb were 3.18 (range, 2.09-4.43) and 0.55 (range, 0.34-0.74), respectively. CONCLUSION: The three- and five-compartment models presented here were successfully used to represent the blood, urine and imaging data. This was evidenced by the small standard errors for the kinetic parameter estimates and R2 values close to 1. As planned future therapeutic trials will involve stem cell support to alleviate hematological toxicities, the development of an approach for estimating doses to other major organs is crucial.
Subject(s)
Carcinoembryonic Antigen/immunology , Indium Radioisotopes/pharmacokinetics , Indium Radioisotopes/therapeutic use , Radioimmunodetection , Radioimmunotherapy , Yttrium Radioisotopes/pharmacokinetics , Yttrium Radioisotopes/therapeutic use , Adult , Aged , Animals , Female , Humans , Male , Mice , Middle Aged , Models, Theoretical , Pilot Projects , Radiation Dosage , Recombinant Fusion Proteins/pharmacokinetics , Recombinant Fusion Proteins/therapeutic use , Tissue DistributionABSTRACT
We evaluated the histopathologic changes of the uterine epithelium in 73 breast cancer patients with tamoxifen stratified by menopausal status. Clinicopathologic data at the time of breast cancer diagnosis and endometrial sampling were analyzed and compared with 122 breast cancer patients not receiving the drug. The incidence of endocervical and/or endometrial polyps was increased in tamoxifen-treated postmenopausal patients compared with untreated patients, 43% (25 of 58) and 24% (16 of 68), respectively (odds ratio=2.46, P=0.02). In contrast, there was no increase in polyps in premenopausal tamoxifen-treated patients. This finding suggests that the effects of tamoxifen on the endometrium may vary with menopausal status.
Subject(s)
Adenocarcinoma/chemically induced , Antineoplastic Agents, Hormonal/adverse effects , Breast Neoplasms/drug therapy , Menopause , Polyps/chemically induced , Tamoxifen/adverse effects , Uterine Neoplasms/chemically induced , Uterus/drug effects , Cross-Sectional Studies , Endometrial Hyperplasia/chemically induced , Epithelium/drug effects , Female , Humans , Middle Aged , Retrospective Studies , Uterus/pathology , Uterus/surgeryABSTRACT
The question of how to include radioactive decay during biological modeling with first-order differential equations was considered. Modeling may involve either experimental data y(t) or decay-corrected data z(t) [identical to exp(lambda t)y(t) where lambda is the decay constant] for each compartment. It is sometimes assumed that the latter are solutions to corresponding purely pharmacokinetic models (no decay). We primarily compared the two analyses in the case where the model did not require simultaneous consideration of both labeled and unlabeled material. A general theorem was found which limits the use of decay-corrected data to pharmacokinetic models containing linear, homogeneous differential equations. By way of verification, an example of this model type was analyzed for a chimeric monoclonal antibody biodistribution in man. Even in this case, statistically significant differences between the two solutions showed that one may find different model parameters depending upon which data set (y or z) was analyzed. For other mathematical forms, the analyst must include the physical decay in all relevant compartments. By analyzing an open, quadratic model, effects of not including decay were seen to be maximized if the biological rate constant was > or = lambda, the physical decay constant. Finally, using monoclonal antibody-antigen reactions, similar discrepancies between the z functions and the pharmacokinetic variables were demonstrated. This result was found to persist even if competitive molecules were included. We conclude that decay-corrected data may be shown, but should not be entered into the modeling equations unless the latter are of the linear, homogeneous form.
Subject(s)
Antibodies, Monoclonal/pharmacokinetics , Models, Biological , Pharmacokinetics , Radioisotope Dilution Technique , Humans , Kinetics , Mathematics , Recombinant Fusion Proteins/pharmacokinetics , Regression Analysis , Time FactorsABSTRACT
It has been shown previously that estrogen receptors (ER) detected by immunohistochemical examination of paraffin-embedded tissue sections could be quantified by computerized image analysis. Several factors were identified that were, in part, responsible for the modest correlation obtained with biochemical assay results. In the present study, 45 formalin-fixed, paraffin-embedded breast carcinomas from a previous study were reevaluated to determine if current methods could provide a better correlation and more consistent results. Sections of the tumors were made to react with estrogen and progesterone receptor antibodies (ER-ICA and PgR-ICA) and the intensity of the stain was quantified using an image analysis system. Vimentin immunostain was used to assess the degree of antigenic loss. Quantitation was performed only on the areas with nuclear staining. The correlation of the estrogen and progesterone receptor values obtained by the dextran charcoal-coated method with the percentages of stained areas and with the intensity of the stain was excellent. The agreement between both methods was 91.1% for estrogen and 86.7% for progesterone receptor values. These results represent a significant improvement compared with those found in a previous study (87% agreement for estrogen receptor). The current approach to estrogen and progesterone receptor quantitation is simplified and eliminates subjectiveness in the selection of the fields for evaluation. The studies are reproducible because discrepancies due to sampling techniques are excluded. Finally, the method validates the technique as a substitute for cytosol-based methods. The results of the two vastly dissimilar assays, the pitfalls of the "gold standard" dextran charcaol-coated assay, and the need for retrospective studies to acquire a range of quantified ER-ICA and PgR-ICA values with clinical significance are discussed.