A monoclonal antibody (B72.3) to adenocarcinoma of the colon and related tumors.
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Adenocarcinoma↗
Biomedical subjects
S M Larson
Publications and source records attributed to S M Larson.
In vitro complex formation and biodistribution of mouse antitumor monoclonal antibody in cancer patients.
The serum clearance and biodistribution of a murine monoclonal antibody were compared to the in vitro complex formation of the antibody with patients' sera. Iodine-125-labeled 9.2.27, an anti-melanoma antibody, was incubated with sera from ten melanoma patients who had received 9.2.27 in an earlier study. Complexes were observed in all patients using size exclusion high performance liquid chromatography and complex formation was partially blocked by nonspecific murine antibody, suggesting the presence of human anti-murine antibody in serum. All patients subsequently underwent imaging studies with [131I] 9.2.27 given intravenously. The serum levels of the antibody obtained after the second administration were inversely correlated with the level of in vitro complex formation. Patients whose serum formed high levels of complex showed a rapid serum clearance, high hepatic uptake, and accelerated whole body clearance and urinary excretion of 131I. This suggests that in patients who receive repetitive administration of murine antibody the serum clearance rate and biodistribution of intravenously injected antibody are altered by antibody complex formation in the serum.
Adult↗
Reduction of background activities by introduction of a diester linkage between antibody and a chelate in radioimmunodetection of tumor.
A diester linkage was added between monoclonal anti-melanoma antibody 96.5 and a diethylenetriaminepentaacetic acid derivative to test if a tumor-to-blood and -to-organ ratio of the injected antibody in nude mice with human melanoma FEM XII xenografts could be increased by the addition of the readily cleavable linkage. Compared to the 111In-labeled antibody DTPA with a peptide linkage, the diester conjugate cleared much faster from the blood and was retained much less in muscle and normal organs such as liver, spleen and kidney over a 48-hr period. On the other hand, the activity retained in the tumor was larger than or similar to that of the peptide conjugate for this time period. This resulted in a 2.5, 2.1, and 2.6 fold increase in a tumor to blood, to liver and to kidney ratio at 48 hr for the diester conjugate as compared to the peptide conjugate. The whole-body biologic half life of the antibody was 36 hr, three times shorter than the peptide conjugate. The external imaging demonstrated a clearly visible tumor at 4 hr and a lower pool activity at 72 hr for the diester conjugate. The peptide conjugate, however, showed a persistant blood-pool activity at 72 hr. The addition of the diester linkage, therefore may be beneficial for imaging tumors in patients at early time intervals after injection.
Animals↗
Measurement of local Mr 97,000 and 250,000 protein antigen concentration in sections of human melanoma tumor using in vitro quantitative autoradiography.
An assay method that uses 125I-labeled monoclonal antibody (MoAb) and in vitro quantitative autoradiography was developed to determine the local concentration of tumor-associated antigens in tissue sections. Human melanoma biopsy specimens were evaluated for the expression of the Mr 97,000 and 250,000 protein antigens using MoAb-96.5 and MoAb-9.2.27, respectively. Tissue sections were incubated in solutions of increasing concentration of 125I-labeled MoAb with or without an excess of unlabeled antibody. Quantitative autoradiography was performed on the sections and compared with 125I standards to determine tumor-bound radioactivity and calculate bound pmol of MoAb per g of tumor. The total binding, nonsaturable binding, and specific binding of 125I-labeled MoAb to tumor were then computed. Specific binding of MoAbs to tumor tissue was saturable in all antigen-positive tumors. The maximal concentration of specific binding of antibody to tissue (Bmax) represented the tissue antigen concentration. Estimates of the Ka of antigen/antibody binding were also made. The reliability of the measurements was confirmed by testing sections from mixtures of antigen-positive and antigen-negative cells.
Antibodies, Monoclonal↗
Brain glucose metabolism in neurologically normal patients with sickle cell disease. Regional alterations.
Neurologic dysfunction is a significant source of morbidity and mortality in the sickle cell diseases, occurring with a prevalence of 6% to 34%. Because changes in brain glucose metabolism may precede gross functional or morphologic alterations, we recently applied the technique of positron emission tomography with fluorodeoxyglucose F 18 in an exploratory study to compare six patients with sickle cell disease without prior neurologic abnormalities (and with normal cranial computed tomographic scans) with six healthy age-matched controls, with respect to overall and regional cerebral metabolic rates for glucose. We found no significant difference in the global metabolic rates for the two groups. However, we observed an unusual clustering of abnormal regional cerebral metabolic rates for glucose in the frontal lobes of these subjects. These results support previous observations that frontal lobe involvement may be quite prevalent in sickle cell disease, even among individuals with normal computed tomographic scans.
Adult↗
Radioimmunoscintigraphy of lymphoma with monoclonal antibodies.
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Animals↗
Gallium-transferrin as a macromolecular tracer of vascular permeability.
Labeling of plasma transferrin with gallium was investigated to determine whether the gallium-transferrin complex could be effectively used as a macromolecular tracer in studies of capillary permeability using Positron Emission Tomography (PET). Three gallium-plasma preparations were tested and 2 h biodistribution studies were performed in rats. The three preparations gave similar blood clearance and tissue distribution data, but the methods used for evaluating gallium-transferrin binding were found to be suboptimal. Gallium clearance from blood was biexpoential with both components faster than that of 125I-albumin. Gallium distribution spaces in all tissues including intracerebral Walker-256 tumors were larger than those of albumin. These results indicate a relative instability of the gallium-transferrin complex in vivo, which appears to preclude its use as an acceptable radiolabeled protein for vascular permeability studies using PET.
Animals↗
Advantages of radioiodine over radioindium labeled monoclonal antibodies for imaging solid tumors.
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Antibodies, Monoclonal↗
Clinical use of a monoclonal antibody to bombesin-like peptide in patients with lung cancer.
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Antibodies, Monoclonal↗
Cerebral necrosis after radiotherapy and/or intraarterial chemotherapy for brain tumors: PET and neuropathologic studies.
Cerebral necrosis after radiotherapy for brain tumors is being recognized as a problem more common than previously estimated. Distinction between this iatrogenic complication and tumor recurrence cannot be made by either CT or MR imaging. By using positron emission tomography (PET) with 18F-deoxyglucose (FDG) we were able to reach a diagnosis of radiation necrosis, later verified, in 10 of 95 patients referred for the purpose of differentiating tumor recurrence from necrosis. The critical PET-FDG feature was focal hypometabolism in the area of necrosis, which contrasted with the hypermetabolism associated with the residual/recurrent tumor. In addition, four cases of cerebral necrosis after supraophthalmic, intraarterial chemotherapy (BCNU) were studied with the PET-FDG method. The area of chemotherapy damage was also characterized by marked hypometabolism. Histology revealed both similarities and differences between radio- and chemonecrosis.
Adolescent↗
Metabolic imaging of human extremity musculoskeletal tumors by PET.
The measurement of glucose utilization rate (GUR) by positron emission tomography (PET) using 18F-2-fluoro-2-deoxy-D-glucose (FDG) is a valuable method to assess the grade of malignancy of brain tumors. We have designed a feasibility trial to determine whether PET could be used to image and predict the grade of malignancy of human extremity musculoskeletal tumors. Five patients with extremity tumors (four soft-tissue tumors and one osteogenic tumor) were studied. Peak and mean apparent GURs were determined in the tumor region. All tumors were subsequently resected and graded in a standard fashion using the NCI grading system. Peak apparent GURs ranged from 3.3 mg/100 g/min to 15.2 mg/100 g/min, with the highest values found in the high grade tumors. Although the number of patients studied was small, a good correspondence was shown between GURs and histopathologic grading. Our results indicate that PET can be used to image and evaluate the metabolic activity of human musculoskeletal tumors.
Adolescent↗
The effect of energy window on cardiac ejection fraction.
ECG gated gamma-ray energy spectra from the left ventricle were created each 50 msec during the cardiac cycle. Nine of ten subjects were studied with a nonimaging Nal probe, and the tenth with a high-resolution Germanium detector. Placing multiple energy windows over the energy spectra, EF was found to vary with the energy window selected. Moving a 20% window across the photopeak produced a roughly linear increase in EF with energy (2.3 EF units per 10 keV increase in energy) in eight of the ten subjects. Dividing the photopeak into a low (126-140 keV) and high-energy (140-154 keV) portion gave significantly different EFs (high energy exceeding low energy by 17%). Increasing the width of a narrow window centered about the photopeak produced negligible change in EF. Examining the energy spectra showed that the small-angle scattered radiation (126-139 keV) was proportionately greater at end systole than at end diastole, after normalizing the spectra to the same photopeak area.
Electrocardiography↗
Fate of gamma-interferon-activated killer blood monocytes adoptively transferred into the abdominal cavity of patients with peritoneal carcinomatosis.
Five patients with colorectal cancer widely metastatic to peritoneal surfaces have been treated i.p. with infusions of autologous blood monocytes made cytotoxic by in vitro incubation with human gamma-interferon. The monocytes were purified by a combination of cytapheresis and counter-current centrifugal elutriation procedures; each week approximately 350 million activated monocytes were given to patients as adoptive immunotherapy by a single i.p. instillation. On the eighth cycle of treatment the trafficking of i.p. infused blood monocytes was studied in two patients by prelabeling the cells with 111In. These activated cells became distributed widely within the peritoneal cavity. Two and 5 days after infusion their position within the peritoneum had not changed. When peritoneal specimens were obtained 36 h after 111In-labeled monocyte infusion, labeled monocytes were demonstrated to be associated with the serosal surfaces by autoradiographic analysis. Scintiscanning structures outside the abdominal cavity revealed that 111In-labeled monocytes infused i.p. did not traffic to other organs during the 5 days of the study. We conclude that i.p. adoptive transfer of autologous killer blood monocytes is an effective way of delivering these cytotoxic cells to sites of tumor burden on peritoneal surfaces in these cancer patients.
Colonic Neoplasms↗
Immunolymphoscintigraphy and the dose dependence of 111In-labeled T101 monoclonal antibody in patients with cutaneous T-cell lymphoma.
Serial gamma camera imaging was performed in 11 patients with cutaneous T-cell lymphoma after s.c. injection between the toes of 111In-labeled T101, a pan T-cell monoclonal antibody. Two of the patients also received 111In-labeled 9.2.27, an isotype-matched control monoclonal antibody. Three doses of T101 (0.1, 0.5, and 1.0 mg), coupled with 0.5 mCi 111In, were used to measure lymph node uptake and dose response. A single 0.5-mg (0.5 mCi) dose of 111In-9.2.27 was used as control antibody to assess nonspecific uptake. Low-dose (0.1 mg) T101 administration produced rapid, intense uptake in inguinal-femoral and iliac nodes with minimal uptake in the paraaortic nodes and liver. The 0.5-mg dose and higher produced consistent uptake in all subdiaphragmatic nodes with greatest accumulation of liver activity at the 1.0-mg dose. In the two control studies, the ratio of specific:nonspecific antibody uptake in the inguinal-femoral, iliac, and paraaortic nodes averaged 7.7,5.9, and 1.9 at 48 h, respectively. In another patient, inguinal-femoral node biopsy contained over 2% of the injected dose of 111In-T101 per gram at 7 days. These findings suggest efficient and specific antibody binding in nodes nearest to the injection site, with progressive uptake of remaining antibody in more distant nodes as proximal sites approach saturation. Higher doses increase overflow of unbound antibody into the systemic circulation. There appears to be an optimal s.c. dose of approximately 0.5 mg (0.25 mg/foot) for T101 immunolymphoscintigraphy of subdiaphragmatic lymph nodes in patients with cutaneous T-cell lymphoma.
Adult↗
Complementation of intracavitary and intravenous administration of a monoclonal antibody (B72.3) in patients with carcinoma.
Monoclonal antibody (MAb) B72.3 has been shown to have selective reactivity for a wide range of carcinomas (colorectal, ovarian, breast, lung, gastric, and endometrial) versus normal adult tissues. 131I-Labeled B72.3 IgG has recently been shown to selectively bind carcinoma lesions when administered i.v. in patients with metastatic colorectal cancer. We report here the first direct comparison of i.p. administered [131I]B72.3 IgG to specifically localize metastatic carcinoma. Three of 10 patients studied were negative for tumor detection by both CAT scan and X-ray but were positive for tumor localization via gamma scanning i.p. administered 131I-labeled MAb B72.3 IgG. Direct analyses of biopsy specimens of carcinoma and normal tissues demonstrated ratios of greater than 70:1 (based on percentage of injected dose/mg) for tumor MAb localization versus normal tissues. Specificity of [131I]B72.3 tumor targeting was demonstrated by the concomitant administration of an equal dose of an 125I-labeled isotype identical (IgG1) control MAb. Simultaneous i.p. administration of [131I]B72.3, and i.v. administration of [125I]B72.3 in individual patients demonstrated: peritoneal implants are targeted more efficiently via i.p. MAb administration, and hematogenously spread and lymph node metastases as well as local recurrences are targeted more efficiently by i.v. administered MAb. No antibody toxicity was observed in any patients. Pharmacokinetics of MAb clearance demonstrated that only 10 to 30% of the i.p. administered MAb was found in plasma. These studies thus demonstrate the efficacy of intracavitary MAb administration as well as the advantage of the concomitant use of intracavitary and i.v. administered MAbs for tumor targeting and for potential MAb guided therapy of metastatic carcinoma.
Adolescent↗
Immunolymphoscintigraphy of pulmonary and mediastinal lymph nodes in dogs: a new approach to lung cancer imaging.
Despite improved resolution with new imaging techniques, surgical confirmation of mediastinal lymph node status is often required for reliable staging of patients with non-small cell lung cancer. Recent scintigraphic studies suggest that s.c. administration of radiolabeled antibodies can be more efficient than the i.v. route for targeting regional lymph nodes in animals and humans. To determine if this approach could be applied to the lymphatics of the lung, we injected both specific and irrelevant radiolabeled monoclonal antibodies via a flexible fiberoptic bronchoscope through the mucosa of lobar bronchi in normal dogs. The injected antibodies were expected to drain by way of local lymphatic vessels toward the central lymph nodes, in effect following the same pathway as do cells metastasizing to these nodes during early regional tumor dissemination. To accomplish this, anesthetized dogs were intubated and then coinjected with the two labeled antibodies [600 microCi/100 micrograms (total)] through a fiberoptic bronchoscope. The animals were serially imaged and then autopsied 14-36 h after injection. Individual hilar and carinal nodes contained over 1% of the injected 131I-labeled specific antibody dose and the average selectivity was 2.5:1 with respect to a coinjected irrelevant IgG. Distant organs (mesenteric lymph node, liver, spleen, bone marrow, and lung parenchyma other than the injection site) contained much less radioactivity, and those sites accumulated a greater fraction of the non-specific labeled antibody. The ratio of iodine-131 to iodine-125 counts between hilar/carinal lymph nodes and abdominal lymph nodes ranged from 15:1 to 100:1. These initial studies indicate efficient delivery of antibody to a subset of the regional nodes via pulmonary lymphatics. They suggest the feasibility of this technique which may be of use in the detection and perhaps therapy of human lung cancer metastases in regional lymph nodes.
Animals↗
Kinetic model for the biodistribution of an 111In-labeled monoclonal antibody in humans.
Using data from 12 patients, we have analyzed the pharmacokinetics of 111In-9.2.27, an antimelanoma monoclonal antibody, following i.v. infusion. Plasma data and scintillation camera images obtained from patients receiving either 1, 50, or 100 mg of monoclonal antibody indicated dose-dependent (i.e., saturable) kinetics. Based on these observations and known immunoglobulin kinetics, we developed a nonlinear compartmental model to describe the biodistribution of 111In-9.2.27 and the other coinjected 111In-associated compounds. The model included (a) three compartments representing intact 111In-9.2.27 ("plasma," "nonsaturable," and "saturable binding" compartments), (b) four compartments representing 111In-diethylenetriaminepentaacetic acid, and (c) one compartment representing 111In in an undetermined chemical form ("extravascular delay" compartment). Analysis of the rate of urinary excretion relative to plasma concentration indicated that the saturable binding compartment was a site for catabolism of monoclonal antibody. Further examination of the urinary data, together with previous studies of the site(s) of immunoglobulin catabolism, suggested that additional elimination took place from either the plasma or the nonsaturable compartment. The model indicated that to fill the saturable sites would require a dose of approximately 0.5 mg and suggested that greater than 3.5 mg would maintain saturation for 200 h. Computer integration of gamma camera counts over the spleen revealed a clear saturable component of uptake, whereas integration over the liver showed no such pattern. The proposed model was fitted to the liver and spleen imaging data by summing fractions of model simulations of each compartment. That analysis confirmed the suspected saturable uptake by the spleen (21% of the saturable binding compartment) and revealed a quantitatively important component of saturation in the liver (35% of the saturable binding compartment) that was not obvious from initial examination of the images. When the results were expressed on a concentration basis, the spleen accounted for 247% of the saturable compartment per kg, whereas the liver accounted for 25%/kg. The bone marrow also showed saturable uptake; hence, the saturable uptake may relate to the sinusoidal blood supply characteristic of liver, spleen, and marrow. The model predicts the dose levels required to overcome saturable background, suggests appropriate doses and schedules for cold loading strategies, and provides a format for explicit inclusion of tumor antigen.
Antibodies, Monoclonal↗
[125I]17-alpha-iodovinyl 11-beta-methoxyestradiol interaction in vivo with estrogen receptors in hormone-independent MCF-7 human breast cancer transfected with the v-rasH oncogene.
[125I]17-alpha-Iodovinyl 11-beta-methoxyestradiol [( 125I]MIVE2) has been evaluated as a potential radiotracer for the diagnostic imaging of estrogen receptor (ER)-positive human breast cancer. In vivo distribution experiments with athymic ovariectomized nude mice bearing human breast tumors revealed an apparent correlation between uptake of 125I-labeled compound and estrogen receptor concentration in the tumors. At 4 h after i.v. injection of [125I]MIVE2, HS578T (ER negative), ZR75-B (intermediate ER), and MCF-7ras (high ER) tumors accumulated 0.320 +/- 0.186, 0.679 +/- 0.467, and 2.6163 +/- 1.0121% injected dose/g, respectively. With coinjection of unlabeled 17-beta-estradiol, levels of radioactivity in MCF-7ras tumors were decreased to 0.4859 +/- 0.1424% injected dose/g, indicating a receptor-mediated process. Peak activity of radioligand in MCF-7ras tumors and uteri was observed at 2 h and was retained for the 8-h time course. Blood and nontarget tissue, such as muscle, revealed a rapid clearance of 125I-labeled compound by 8 h. Eight hours after injection, uterus and tumor-to-blood ratios were calculated to be 225 and 21, respectively. Also, MCF-7ras tumors were shown to accumulate 6.5-fold more radioactivity than muscle. These data suggest that [125I]MIVE2 has the capability of interacting specifically and with high affinity with estrogen receptors in human breast tumors in nude mice and may possibly be used for imaging receptor-positive tumors in breast cancer patients with very low serum estrogen levels. Selective uptake of compound in MCF-7ras tumors emphasizes the usefulness of an estrogen receptor-positive tumor model which has a unique ability to grow in a host system without circulating estrogens.
Animals↗