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Biomedical subjects

S E Halpern

Publications and source records attributed to S E Halpern.

At least 37 records · Page 2Linked to original sources
PubMed1986

Tissue distribution and serum kinetics of T101 monoclonal antibody during passive anti-cancer therapy.

We have administered fifty-six 24 hr infusions of the anti-human T-cell monoclonal antibody T101 to 10 patients with cutaneous T-cell lymphoma (CTCL) and 6 patients with chronic lymphocytic leukemia (CLL) in doses of 10, 50, 100, 150, and 500 mg. The larger doses of T101 resulted in higher, more persistent serum T101 concentrations, and CTCL patients generally developed higher serum T101 levels than CLL patients given equivalent doses. The presence of host anti-mIgG antibodies prior to infusion was associated with decreased serum concentrations of T101. Treatments that demonstrated measurable serum T101 levels were also associated with in vivo T101 binding and cytodestruction of circulating target cells. Immunofluorescence analysis of bone marrow and lymph node biopsies in CLL, and skin biopsies in CTCL, suggested that T101 had reached extravascular tumor sites. Infusion of 111In-conjugated T101 showed uptake in the liver, spleen, lymph nodes, and (in CTCL) skin infiltrates. Our data demonstrate the tissue distribution of T101 and suggest that immunoconjugates of T101 with toxins, drugs, or radioisotopes may result in better therapeutic responses.

Antibodies, Monoclonal↗
PubMed1986

The advantages and limits of indium-111 labeling of antibodies. Experimental studies and clinical applications.

Radiolabeling of antibodies with In-111 has now been accomplished to the point that it is highly reproducible, achieves excellent labeling efficiency, and does not damage the antibody. Use of In-111 for radioimmunodetection is advantageous because of the excellent imaging characteristics of the In-111, moderate radiation dose, ease of labeling, and appropriate half-life. The liabilities of the In-111 method include slightly greater cost of the radionuclide, slow clearance of background sites, and a shelf life requiring it to be ordered on a weekly basis. When all characteristics of the radionuclide are taken into account, it appears to be superior to I-131 for radioimmunoimaging. A controlled study using iodinated and Indium labeled antibodies in the same group of patients needs to be done to accurately access how well the two function for tumor detection.

Antibodies↗
PubMed1986

Tumor size: effect on monoclonal antibody uptake in tumor models.

Studies were performed to determine the effect of tumor size on the incorporation of radiolabeled monoclonal antitumor antibodies (MoAbs) into human tumors growing in nude mice. The colon tumors ranged in size from 0.03-1.6 g, the melanoma from 0.1 to 6.7 g, and the lymphoma from 0.06 to 10.2 g. Indium-111 was primarily used as the radiolabel, however, both 125I and 111In were used as tracers for the MoAb in one experiment. The per g radiopharmaceutical uptake by tumors was inversely proportional to tumor size when tumor specific MoAb was administered. This finding was independent of the radiolabel and was demonstrable when the mice bore two tumors of differing size. When the MoAb was not specific for the tumor, the data were less well defined and a statistically significant correlation with size did not occur. These data are strong evidence for a decrease in per g uptake of labeled tumor specific antibodies as tumors increase in size.

Animals↗
PubMed1986

Continuous infusion of T101 monoclonal antibody in chronic lymphocytic leukemia and cutaneous T-cell lymphoma.

We report results of 24-h continuous infusions of murine monoclonal antibody T101 in six patients with chronic lymphocytic leukemia (CLL), and 10 with cutaneous T-cell lymphoma (CTCL), at doses of 10, 50, 100, or 500 mg. Similar side-effects were seen in CLL and CTCL, including direct toxic effects of therapy, such as fever, sweats, and chilling, and a 30% frequency of allergic manifestations. In vivo binding of T101 to target cells in blood, skin, lymph nodes, tumor masses, and bone marrow was demonstrated. Antigenic modulation occurred rapidly in all cases, and persisted throughout the infusion period. Peak serum T101 levels for equivalent doses were somewhat higher, and persisted longer in CTCL, perhaps because of differences in the number of circulating target cells. Antimouse antibodies were demonstrated in 5 of 10 CTCL vs. 0 of 6 CLL patients. In all five cases, there was a substantial component of T101 specificity in the antimouse response. Brief objective clinical responses were observed in 4 of 10 CTCL and 2 of 6 CLL patients. Acute anti-tumor effects of T101 were substantially more dramatic in CTCL than CLL, but appeared limited by antigenic modulation and the emergence of antimouse antibodies. In view of the in vivo binding and modulation, more durable anti-tumor effects may be achievable with cytotoxic immunoconjugates of this monoclonal antibody.

Antibodies, Monoclonal↗
PubMed1986

Toxicities and side effects associated with intravenous infusions of murine monoclonal antibodies.

Toxicity was assessed during and following 186 infusions of various murine monoclonal antibodies (MoAbs) in 82 patients afflicted with 10 different malignancies. Doses ranged from 0.5 to 500 mg per infusion and were administered over 0.25-24 h. Reactions of varying degrees were noted in 27 patients (33%) during or following 57 (31%) infusions. For antibodies that reacted with circulating cells, toxicity was seen in 20/82 of the first infusions compared with 0/55 for patients receiving antibodies that did not react with circulating cells. A 25% decrease in white blood cells (WBC) was associated with side effects in 40/66 courses whereas only 9/81 courses were associated with any sort of toxicity when the WBC decreased by less than 25%. Fevers, rigors, chills, and diaphoresis were observed in 21-23% of patients, but only in association with removal of circulating cells that bound the antibody. Presumed hypersensitivity reactions, including urticaria, pruritus, bronchospasm, and anaphylaxis occurred in 15 patients (18%). The two episodes of bronchospasm and single episode of anaphylaxis occurred in patients treated more than once, at least 2 weeks after a previous treatment. There was no clear relationship between dose or rate of infusion and toxicity for these antibodies. We conclude that murine MoAbs can be given with an acceptable frequency of serious allergic reactions and that the biologic effects of specific antibody-antigen reactions may be a more significant source of toxicity for such antibodies.

Adolescent↗
PubMed1986

In vitro and in vivo tumor models for studies of distribution of radiolabelled monoclonal antibodies and fragments.

Colon carcinoma multicellular spheroids were incubated in vitro with radiolabelled MAbs. The more rapid penetration of fragments as compared to intact MAbs was clearly demonstrated. For the study of antibody localization in tumors in vivo, the model of nude mice with ligated kidneys was used. Although very artificial, this model allowed to demonstrate that, without urinary excretion, Fab fragments accumulated more rapidly into the tumor than intact MAbs and disappeared faster from the blood. This difference was less striking for F(ab')2 fragments. In the liver a decreased accumulation of both types of fragments as compared to intact MAbs was observed. Concerning radioimmunotherapy we think that Fab fragments are not useful because of their too short half-life in the circulation and in tumor and because they will probably be too toxic for the kidneys. Intact MAbs and F(ab')2 fragments have each their advantages. Intact MAbs show highest tumor accumulation in mice without ligated kidney, however, they remain mostly on the periphery of tumor nodules, as shown by autoradiography. F(ab')2 fragments have been found to penetrate deeper into the tumor and to accumulate less in the liver. It might be therefore an advantage to combine intact MAbs with F(ab')2 fragments, so that in the tumor two different regions could be attacked whereas in normal tissues toxicity could be distributed to different organs such as to the liver with intact MAbs and to the kidney with F(ab')2 fragments.

Animals↗
PubMed1985

Radioimmunodetection of melanoma utilizing In-111 96.5 monoclonal antibody: a preliminary report.

The murine 96.5 monoclonal antimelanoma antibody (MoAb) was labeled with In-111, and 1-20 mg were administered to 21 patients who had proved or suspected melanoma metastases. One patient was studied twice. In four patients, unlabeled 96.5 MoAb was administered prior to the radiopharmaceutical. All of the patients tolerated the procedure without toxicity regardless of the mass of MoAb administered. The scans were interpreted by two observers, one with full knowledge, the other with no knowledge of the cases. Increasing the MoAb mass or preinfusing unlabeled MoAb prior to the administration of In-111 MoAb resulted in a prolongation of the serum half time, and appeared to improve tumor detection. Lesions were best seen at 72 hours after infusion or later. In all patients who had metastatic disease, at least one tumor site was apparent. Fifty-six per cent of known lesions 1.5 cm or greater in size were detected by the physician who had knowledge of the cases when data from all doses were considered. There were eight lesions detected that were not suspected in the workup of the patient. When these are included, the detection rate rises to 61%. Forty-nine per cent were detected by the other physician. Subtraction techniques were not employed. Lesions were often better seen with single photon emission computed tomography than with planar imaging techniques. The 96.5 In-111 MoAb appears to have utility for the detection of metastatic melanoma. Further clinical evaluation of 96.5 In-111 MoAb is warranted.

Adolescent↗
PubMed1985

Athymic mouse model of a human T-cell tumor.

Because of the large number of different immunoconjugates which can be produced from monoclonal antibody-directed anti-cancer therapy, it would be useful to have in vivo tumor models to compare such preparations. Although historically human leukemias-lymphomas have been difficult to establish in athymic mice we have succeeded in establishing human T-cell tumors from primary MOLT-4 cultures in 290 of 353 animals and have successfully transferred tumors in 42 of 45 animals during ten serial passages. The potential utility of this model for testing immunoconjugates of murine monoclonal antibody T101 have been confirmed by: (a) in all 148 tumors sampled including all passaged tumors the human T-cell antigen, T65, was expressed in a manner identical to that of cultured cells; (b) 111In-T101 was concentrated preferentially in the tumor; and (c) T101 injected by both the i.p. and i.v. routes bound to tumor and induced antigenic modulation to the same extent as that observed previously in vitro and in human studies.

Animals↗
PubMed1985

In vivo kinetics of radiolabeled monoclonal anti-CEA antibodies in animal models.

Studies were performed to determine the effect of the radiolabel and circulating carcinoembryonic antigen (CEA) on the pharmacodynamics of monoclonal anti-CEA antibodies (MoAbs). The studies were performed in normal BALB/c mice and in nude mice bearing human colon tumors. Three different tumors were used, each of which produced CEA levels characteristic of that particular tumor's secretory rate. The CEJ-326 MoAb labeled with either 111In or 125I was used in all studies. Circulating CEA induced the removal of 125I and 111In MoAbs from the vascular compartment. Liver concentrations of 111In increased and 125I levels decreased as the CEA secretory rate of the tumor rose. This indicates that circulating CEA complexes form in the vascular compartment which, in an animal model, are removed by the liver and spleen. This results in decreased tumor uptake of the labeled MoAb. The iodinated MoAb complexes are dehalogenated while the 111In is retained by the liver. This dehalogenation may account for the relatively low liver activity observed in radioimmunoimaging with intact radioiodinated anti-CEA MoAbs, provided the CEA complexes are similarly removed from the vascular compartment by the human liver.

Animals↗
PubMed1984

Single photon emission computed tomograms of the liver: normal vascular intrahepatic structures.

Because of the high target-to-background contrast obtained with single photon emission computed tomography (SPECT), normal intrahepatic vessels approximately 2 cm in diameter may appear as distinct focal defects in tomographic sections throughout the liver even though normal vessels rarely cause such defects on planar images. To assess this problem, five subjects without evidence of liver disease underwent tomography of the liver with Tc-99m sulfur colloid (TSC) and on a separate occasion tomography of the intrahepatic blood pool with Tc-99m autologous red blood cells (RBC). In each case, well demarcated defects were obvious in contiguous TSC liver tomograms in various planes. Direct comparison with RBC tomograms showed that all of these defects corresponded to intrahepatic veins, typically the right portal vein, its posterior branch, and the left portal vein. Knowledge of the intrahepatic vascular anatomy in a variety of tomographic planes, with examination of each defect in multiple orthogonal planes is necessary to avoid false positive interpretations. In some instances a study with RBC may also be required for more conclusive evaluation of defects seen on TSC liver tomograms.

Diagnostic Errors↗
PubMed1984

In-111-leukocyte scintigraphy for detection of infection associated with peritoneal dialysis catheters.

In-111-labeled leukocytes were administered to 13 patients on continuous ambulatory peritoneal dialysis in order to locate catheter-associated infections. Using a marker to indicate the catheter exit site, infections of the catheter tunnel were correctly identified prior to surgery in 4 patients with relapsing peritonitis and infections of the exit site were diagnosed in 5 out of 7 patients. There were no false positives or negatives as documented by surgery or follow-up. The authors conclude that In-111-leukocyte scintigraphy appears to be accurate in diagnosing peritoneal infections of the dialysis catheter tunnel.

Adolescent↗
PubMed1984

Carcinoembryonic antigen production, secretion, and kinetics in BALB/c mice and a nude mouse-human tumor model.

Carcinoembryonic antigen (CEA) is currently being used as a target antigen in the radioimmunodetection of cancer. Circulating CEA may adversely affect the outcome of such studies by formation of intravascular immune complexes. The following studies were undertaken to expand our knowledge of the production, secretion, and pharmacokinetics of CEA, since these factors should have a direct bearing on the serum levels of CEA encountered in radioimmunodetection. The production of CEA was assessed in nude mice given implants of the T-380 CEA secreting human colon tumor. Serum CEA rose linearly as the tumors enlarged; however, the concentration of CEA per g of extracted tumor remained constant throughout the weight range studied. The secretory rate of the T-380 tumor was determined by surgically removing all blood flow to the liver and gastrointestinal tract of the nude mouse model. This procedure removes the known sites of CEA degradation. Serum CEA levels rose progressively following surgery, the values being directly related to the tumor size. The secretory rate was also proportional to tumor size but was a constant 13.8 +/- 3.6 (S.D.) ng/g tumor/hr when expressed on a per g tumor basis. To determine if the serum levels of CEA observed in patients could be due to unique differences in the clearance rates of each patient's CEA, serum from three patients with CEA levels of 2150, 709, and 58 ng/ml was administered i.v. to groups of mice at the original and diluted concentrations. The kinetics of all samples followed a single exponential clearance pattern with a half-time of about 2.5 hr. This was dramatically different from the kinetics of tumor-extracted CEA which exhibited a multiexponential pattern, the first component having a half-time of 3 min. These data suggest that CEA secreted by a tumor is in some way different from that adhering to the tumor. If the secreted CEA truly has a monoexponential clearance with a fixed rate as the experiments suggest, the absolute values of serum CEA are either entirely a function of the tumor secretory rate, or else the product having the short half-time is not measured in serum samples obtained from patients.

Animals↗
PubMed1984

Lack of radioimmunodetection and complications associated with monoclonal anticarcinoembryonic antigen antibody cross-reactivity with an antigen on circulating cells.

Characterization of several high-affinity murine monoclonal anticarcinoembryonic antigen (CEA) antibodies suggested good specificity except for cross-reactivity with an antigen on granulocytes and erythrocytes which was different from the previously described normal cross-reacting antigen of granulocytes. In vivo studies in athymic mice using an indium conjugate of an anti-CEA monoclonal antibody (MoAb) revealed excellent specific uptake in colorectal carcinoma xenografts. Studies were conducted in humans to determine the limitations produced by the cross-reactivity with granulocytes and erythrocytes. Patients with metastatic colorectal cancer received 3 to 6 mg of anti-CEA MoAb over 10 min or 2 hr. In five of six trials, the MoAb infusion was associated with a 40 to 90% decrease in circulating granulocytes and systemic toxicity including fever, rigors, and emesis. One patient had no change in cell count and had no toxicity. Radionuclide scans with 111In-anti-CEA MoAb showed marked uptake in the spleen when cells were eliminated, and in the liver, especially when pretreatment CEA levels were high. Metastatic tumor sites failed to concentrate the isotope. This study emphasizes the potential limitations for radioimmunodetection and/or radioimmunotherapy imposed by reactivity with circulating cells, and suggests that certain toxic reactions associated with MoAb infusions are related to destruction of circulating cells rather than allergic reactions to mouse protein. It also emphasizes how variables such as dose and binding affinity of antibody, radioisotope used, and assessment at different observation points can obscure lack of antibody specificity.

Animals↗
PubMed1983

Stability, characterization, and kinetics of 111In-labeled monoclonal antitumor antibodies in normal animals and nude mouse-human tumor models.

Monoclonal antibodies (MoAbs) against carcinoembryonic antigen were successfully radiolabeled with 111In, and the radiopharmaceutical was characterized in vitro and in normal and tumor-bearing mice. The 111In-MoAb proved to be stable in vitro and in vivo under normal conditions, although instability could be induced in vitro with large quantities of iron-free transferrin. Animal distribution studies with 111In-MoAb demonstrated tumor localization superior to 67Ga and pharmacokinetics that were highly similar to those of endogenously labeled 75Se-MoAb. The 111In-MoAb followed first-order kinetics and fit a two-compartmental model when studied in nude mice bearing human colon tumors known to express carcinoembryonic antigen. Significant quantities of radiolabel appeared in tissues other than tumor, with liver and skin having the highest concentrations. Sufficient tumor/background ratios were formed for scanning purposes. The data indicate that 111In-MoAb may prove to be effective as a radiopharmaceutical for tumor imaging.

Animals↗
PubMed1982

Limitations of renal function scanning in acute obstruction.

This study was designed to determine if technetium-99m penicillamine (TPEN), could be used to predict recoverable function in dogs with acute obstruction. Renal accumulation of TPEN was measured in four control dogs, in four dogs with acute obstruction lasting 7-14 days, and in the same four dogs following a variable recovery period of 15-63 days. The relative renal uptake of TPEN in vivo showed good agreement with the relative uptake in vitro and both measurements correlated closely with the relative inulin clearances in the normal and in the post obstructed kidneys. The uptake of TPEN in the obstructed kidney following 7-14 days of obstruction averaged 6.8% of the total renal uptake. After relief of the obstruction and a variable recovery period the relative uptake of TPEN in the post obstructed kidney had increased to a mean of 29.5%. These results indicate that TPEN scans should not be used during acute obstruction to predict recoverable function. The observations noted in the study almost certainly apply to similar chelating agents such as dimercaptosuccinic acid (DMSA) and probably to other renal radiopharmaceuticals as well.

Animals↗
PubMed1980

The effect of parathyroid hormone on technetium-99m pyrophosphate distribution in rats.

Sprague-Dawley rats were treated with varying quantities of parathyroid hormone for 1--3 days, then sacrificed at periods ranging from 1--6 h after administration of 99mTc-pyrophosphate. Very little increase in bone accumulation of tracer occurred with this treatment. A small, but obvious decrease occurred in the blood levels of 99mTc-pyrophosphate and a smaller and less consistent decrease was affected in the muscle levels of the radiopharmaceutical. The overall result was an improvement in the bone/blood and bone/muscle ratios. It is suggested that the basis of the "supernormal" bone scan of hyperparathyroidism is achieved by this mechanism and that the increased bone uptake of other ions in response to parathyroid hormone is not shared by 99mTc-pyrophosphate.

Animals↗