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Biomedical subjects

D M Goldenberg

Publications and source records attributed to D M Goldenberg.

At least 109 records · Page 6Linked to original sources
PubMed1996

Antibody penetration of tumor GS-7 xenografts in nude mice: a model for mucinous adenocarcinoma of the colon.

A new cell line derived from a human adenocarcinoma of the colon, GS-7, was propagated as a s.c. tumor in nude mice. This tumor histologically is a mucinous adenocarcinoma (also designated mucoid or colloid) with characteristic large mucin pools that are not lined by an epithelial layer but may contain scattered, randomly distributed cancer cells. Ten to 20% of human colorectal adenocarcinomas are of this histological type, but rapidly growing xenografts with this histology have been rarely used experimentally. This tumor, therefore, constitutes a useful model for similar human tumors. The mucin pools contain large amounts of carcinoembryonic antigen and tumor-associated glycoprotein 72, and the cells express epithelial glycoprotein 2 on their surface. The ability of antibodies injected i.v. to penetrate this tumor was investigated, using both biotinylated and radioiodinated antibodies (Abs). The results demonstrate that Abs can effectively penetrate the mucin pools, and that large amounts of Ab can localize there. This tumor type may have advantages as a target for certain forms of experimental immunotherapy.

Adenocarcinoma, Mucinous↗
PubMed1996

Clinical evaluation of tumor targeting with the anticarcinoembryonic antigen murine monoclonal antibody fragment, MN-14 F(ab)2.

BACKGROUND: The initial clinical experience with the second-generation, high-affinity, MN-14 immunoglobulin (IgG) anticarcinoembryonic antigen (CEA) monoclonal antibody (MoAb) in patients with CEA-producing tumors was reported previously. A bivalent fragment of this MoAb, MN-14 F(ab)2, was prepared, and its pharmacokinetics, targeting properties, dosimetry, and immunogenicity were investigated. METHODS: MN-14 F(ab)2(0.6-29 mg) was labeled with 131I(7.7-269 millicuries and injected into 28 patients with CEA-producing cancers. External scintigraphy was used to evaluate tumor targeting. Quantitative external scintigraphy methods were used to determine the organ and tumor radiation doses. RESULTS: The overall sensitivity of tumor targeting on a lesion basis was 86%, similar to that reported previously for MN-14 whole IgG. The biologic T1/2's for the fragment in the blood and total body (in hours) were 16.8 +/- 4.1 and 59.4 +/- 9.4, respectively, compared with 27.3 +/- 15.7 and 69.6 +/- 32.2 reported for MN-14 IgG. Depending on the protein dose given, high plasma CEA levels (>100ng/ML) resulted in a significant alteration of MoAb pharmacokinetics and organ dosimetry. Individual tumors received an average dose of 10.7 +/- 7.3 centigray [cGy]/mCi, and the tumor-to-total body, red marrow, lung, liver, and kidney dose ratios were 16.8 +/- 11.1, 5.6 +/- 3.6, 5.1 +/- 3.9, 6.0 +/- 3.8, and 3.1 +/- 2.0, respectively (mean + standard deviation [SD]). Only 9 of 18 patients (50%) injected with >4 mg (range: 4-52.1 mg) of MN-14 F(ab)2 developed significant levels of human antimouse antibodies, suggesting that the F(ab)2 may be less immunogenic than the intact IgG. CONCLUSIONS: MN-14 F(ab)2 exhibits a similar targeting sensitivity and tumor dose as reported previously for the IgG form. The lower red marrow doses combined with lower immunogenicity expected for this agent, may make it a suitable alternative for future imaging and therapeutic applications.

Adolescent↗
PubMed1996

Factors influencing the pharmacokinetics, dosimetry, and diagnostic accuracy of radioimmunodetection and radioimmunotherapy of carcinoembryonic antigen-expressing tumors.

The aim of this study was to examine factors that may influence the pharmacokinetics, diagnostic accuracy, and dosimetry in radioimmunodetection and radioimmunotherapy with anti-carcinoembryonic antigen (CEA) monoclonal antibodies (mAbs). Data from 275 patients with CEA expressing tumors were analyzed retrospectively. Of these, 69 patients devoid of human antimouse antibody (i.e., 31 colorectal, 9 lung, 7 breast, 4 ovarian, 6 pancreatic, 9 medullary thyroid, 1 gallbladder, and 1 salivary gland cancer, and 1 primary tumor of unknown origin) underwent a low-protein-dose diagnostic study (0.3-2.6 mg of protein; 6.8-28.8 mCi 131I-labeled IgG or fragments), followed within 4 weeks by a high-protein-dose therapy injection (4.0-27.5 mg of protein; 29.8-238.9 mCi). The anti-CEA antibodies NP-4 (Ka=10(8)M-1) and MN-14 (ka=10(9)M-1) were used. Plasma clearance, the molecular composition of radioactivity in the plasma, and the cumulated activity in organs and tumors were determined. Radiation doses were derived from the Medical Internal Radiation Dose scheme. At a low-protein dose and over a similar range of plasma CEA, a significantly higher percentage of MN-14 than of NP-4 was complexed with circulating CEA, consistent with its higher affinity. Complexation was reduced with increasing protein doses. However, the targeting sensitivity was not affected. Profound differences were found in the clearance of the antibody between different types of cancer. Colorectal cancer patients cleared the antibody significantly faster from blood (T1/2=17.6+/-12.6 versus 44.2 +/- 23.7 h) and whole body (t1/2= 53.2 +/- 30.1 versus 114.6+/-59.7 h) than all other tumor types (P <0.001). Consequently, significantly lower red marrow (2.1 +/- 1.0 cGy/mCi versus 4.3 +/- 1.6 cGy/mCi) and whole-body doses (0.5 +/- 0.3 cGy/mCi versus 1.0 +/- 0.4 cGy/mCi) were seen in colorectal cancer patients as compared with other tumor types (P < 0.001). This clearance is probably due to hepatic metabolism of the immune complexes. Clearance rates were especially high in patients with colorectal cancer having large liver metastases and elevated liver enzymes (rapid hepatic clearance with liberation of free I-). In contrast, a disease-stage and plasma CEA-matched cohort of colorectal cancer patients, examined with the 131 I-labeled anti-colon-specific antigen p mAb Mu-9, showed normal murine IgG pharmacokinetics (n=22;3 of them compared intraindividually to MN-14). Only in colorectal cancer patients did complexes between mAb and CEA tend to clear rapidly, whereas Mu-9 had normal kinetics in these patients. This suggests that different CEA-expressing cancer types may produce heterogeneous CEA molecules and that the variability in mAb clearance is due to varying clearance rates of these different circulating CEA subspecies. Disease-related alterations in antibody metabolism are unlikely, given that only anti-CEA antibodies exhibit this phenomenon.

Adolescent↗
PubMed1996

Rapid imaging of infections with a monoclonal antibody fragment (LeukoScan).

The diagnostic accuracy for imaging infection with a technetium-99m-labeled antigranulocyte Fab' fragment (LeukoScan) was prospectively examined in a multicenter study. Scintigraphy was performed in 53 patients at 1 to 6 hours and at 24 hours after injection of the labeled antibody fragment. Thirty-nine sites of infection were detected and confirmed by histologic study, cytologic study, other imaging procedures, or by followup. Thirty-eight of the 53 patients also were studied with technetium-99m-Exametazim or indium-111-oxine labeled leukocytes within 1 week of the LeukoScan study. In 21 patients with 25 osteomyelitic lesions, LeukoScan recognized 13 of the lesions as being true positive ones, 10 as being true negative ones, and 2 as being false negative ones, whereas the leukocyte scan showed 9 true positive results, 5 true negative results, and 2 false negative ones. Sensitivity specificity, and diagnostic accuracy of LeukoScan were 90.0 %, 84.6 %, and 87.9 %; and with autologous leukocyte scintigraphy were 83.9%, 76.5%, and 81.3%, respectively. The sensitivity of LeukoScan was independent of the amount of the labeled antibody injected (0.1 - < 0.5 mg, 96.2%; 0.5 - < 0.9 mg, 80.0%; 0.9 - 1.0 mg, 77.8%). False positive lesions were detected in a periprosthetic calcification, a frontal hyperostosis, and 2 periprosthetic hips that had loosened. Human antimouse antibody could not be detected in any of the 13 patients tested 1 or 3 months after injection. LeukoScan is suitable for imaging infectious lesions and may have diagnostic advantages compared with autologous leukocyte scintigraphy.

Adult↗
PubMed1996

Thyroid radiation doses during radioimmunotherapy of CEA-expressing tumours with 131I-labelled monoclonal antibodies.

A number of radioimmunotherapy (RAIT) trials with iodinated antibodies have shown a high variability in the radiation doses to the thyroid. Therefore, the aim of this study was to evaluate which factors influence these thyroid doses during RAIT with 131iodinated monoclonal anti-carcinoembryonic antigen (CEA) antibodies. Data from 36 patients with CEA-expressing tumours were analysed. The patients underwent RAIT with the 131I-labelled IgG1 anti-CEA antibody, MN-14 (Ka = 10(9) l mol-1) or its F(ab')2 fragment (activity range 45.8-220.0 mCi). The thyroid was blocked with 120 mg iodine (lugol's orSSKI solution) and 400 mg perchlorate per day, starting 1 day prior to the first study. Blood clearance and molecular composition of labelled plasma compounds were determined by blood sampling and size-exclusion high-performance liquid chromatography analysis. The cumulated activities of tissues were determined from daily imaging and blood clearance data. Doses were derived from the MIRD scheme. Thyroid radiation doses showed a high variability, between 1.2 and 37.7 cGy mCi-1 (mean +/- S.D.: 11.1 +/- 8.3 cGy mCi-1), corresponding to absolute doses between 2.5 and 43.6 Gy. However, the maximal iodine uptake in the thyroid was 2.4 +/- 1.9 microCi mCi-1 (range 0.2-10.0 microCi mCi-1), which was less than 1% of the injected activity, indicating that more than 99% of the thyroid was blocked in all cases. No correlation was found between these thyroid doses and conditions leading to an enhanced exposure to free radioiodine, such as unbound I- in the mAb preparation, rapid metabolic breakdown of the labelled antibody due to human anti-mouse antibodies (HAMA), or immune complex formation with circulating antigen. However, a relationship between the thyroid doses and the patients' compliance in taking their Lugol's and perchlorate blocking medications, as well as to a relatively high variability in the biological half-life of the iodine in the thyroid (range from 31.1 h to virtual infinity), is indicated. No rising TSH titres or other signs of (latent) hypothyroidism were seen in these patients during a 2 year follow-up period. Longer follow-up was not possible because of the terminal condition of most of the patients. These data show that thyroid doses in an appropriately blocked individual given a standard, non-myeloablative dose of RAIT, are generally lower than those assumed to be required to cause late hypothyroidism. Even if higher activities are used, potential hypothyroidism may be overcome easily by hormone replacement. Thyroid doses are independent of parameters leading to an enhanced exposure of the thyroid to free radioiodine, suggesting that patient compliance in taking their blocking medication may be the most crucial factor for reducing thyroid doses in RAIT with 131I-labelled antibodies.

Adenocarcinoma↗
PubMed1996

Improved detection of medullary thyroid cancer with radiolabeled antibodies to carcinoembryonic antigen.

PURPOSE: This investigation was undertaken to assess the targeting of established and occult medullary thyroid cancer (MTC) with radiolabeled monoclonal antibodies (MAbs) reactive with carcinoembryonic antigen (CEA). PATIENTS AND METHODS: Twenty-six assessable patients with known (n = 17) or occult (n = 9) MTC were studied with radiolabeled anti-CEA MAbs. Scintigraphic images were collected to determine targeting of tumor lesions. RESULTS: The targeting results of technetium 99m (99mTc)-,iodine 123 (123I)-, and iodine 131 (131I)-labeled anti-CEA antibodies (all directed against the same epitope of CEA) indicated that all these reagents were capable of detecting established and occult MTC. The sensitivity for detection of known sites of disease ranged from 76% to 100% for the various anti-CEA MAbs used, when compared with computed tomography (CT), magnetic resonance imaging (MRI), bone scan, or other imaging modalities. Moreover, the antibody scan was positive in seven of nine patients with occult disease (patients with negative conventional imaging studies, but who had elevated calcitonin and/or CEA levels). Three of seven patients underwent surgery and the disease was confirmed by histopathology in all three. CONCLUSION: Anti-CEA MAbs are excellent agents for imaging recurrent, residual, or metastatic MTC. The high lesion sensitivity in patients with known lesions, combined with the ability to detect disease, may make these agents ideal for staging patients, monitoring disease pretherapy or posttherapy, and especially for evaluating patients with recurrent or persistent hypercalcitonemia or CEA elevations after primary surgery. Analogous to radioiodine in the evaluation of patients with differentiated thyroid cancer, radiolabeled anti-CEA MAbs may achieve a similar role in diagnosing and monitoring patients with MTC.

Carcinoembryonic Antigen↗
PubMed1996

Clinical utility of external immunoscintigraphy with the IMMU-4 technetium-99m Fab' antibody fragment in patients undergoing surgery for carcinoma of the colon and rectum: results of a pivotal, phase III trial. The Immunomedics Study Group.

PURPOSE: To assess the performance and the potential clinical impact of a new antibody imaging agent, CEA-Scan (Immunomedics Inc, Morris Plains, NJ), in 210 presurgical patients with advanced recurrent or metastatic colorectal carcinomas. METHODS: CEA-Scan, an anti-carcinoembryonic antigen (CEA) Fab antibody fragment labeled with technetium-99m-pertechnetate (99mTc), was injected intravenously (IV), and external scintigraphy was performed 2 to 5 and 18 to 24 hours later. Imaging with conventional diagnostic modalities (CDM) was also performed, and findings were confirmed by surgery and histology. RESULTS: The sensitivity of CEA-Scan was superior to that of CDM in the extrahepatic abdomen (55% v 32%; P = .007) and pelvis (69% v 48%; P = .005), and CEA-Scan findings complemented those of CDM in the liver. Among 122 patients with known disease, the positive predictive value was significantly higher when both modalities were positive (98%) compared with each alone (68% to 70%), potentially obviating the need for histologic confirmation when both tests are positive. Imaging accuracy also was significantly improved by adding CEA-Scan to CDM. In 88 patients with occult cancer, imaging accuracy was enhanced significantly by CEA-Scan combined with CDM (61% v 33%). Potential clinical benefit from CEA-Scan was demonstrated in 89 of 210 patients. Only two patients developed human antimouse antibodies (HAMA) to CEA-Scan after a single injection, and none of 19 assessable patients after two injections. CONCLUSION: CEA-Scan affords high-quality, same-day imaging, uses an inexpensive and readily available radio-nuclide, adds clinically significant information in assessing extent and location of disease in colorectal cancer patients, and only rarely induces a HAMA response.

Antibodies, Monoclonal↗
PubMed1996

Radioimmunotherapy of medullary thyroid cancer with iodine-131-labeled anti-CEA antibodies.

UNLABELLED: This study evaluates the pharmacokinetics, dosimetry, toxicity and therapeutic potential of radiolabeled NP-4 and MN-14 anti-CEA antibodies in medullary thyroid cancer (MTC). METHODS: Eighteen patients with advanced MTC entered exploratory clinical studies with therapeutic doses of 131I-labeled NP-4 and MN-14 murine monoclonal antibodies (MAbs) reactive with carcinoembryonic antigen (CEA). Doses administered ranged from 46 mCi for 131I-MN-14 lgG to 195 mCi for 131I-MN-14 F(ab)2 in patients negative for human anti-mouse antibodies (HAMA). RESULTS: The radioconjugate blood half-life (T1/2) for the whole lgG was 42.5+/-5.0 hr compared to 18.8+/- 4.1 hr for the bivalent fragments. Tumor doses of 17.5+/-11.0 and 11.4+/-6.3 cGy/mCi were estimated for 131I-MN-14 lgG and F(ab)2, respectively. Tumor/red marrow dose ratios exceeded 3:1 for most lesions. Red marrow doses of up to 350 cGy generally could be delivered with < grade 4 toxicity. Seven of 14 evaluable patients showed evidence of anti-tumor effects lasting up to 26 months, based on physical exam, tumor markers or computed tomography. CONCLUSION: This study demonstrates that anti-CEA MAbs may be suitable for radioimmunotherapy of metastatic or recurrent MTC.

Adolescent↗
PubMed1996

Radioimmunotherapy of patients with small-volume tumors using iodine-131-labeled anti-CEA monoclonal antibody NP-4 F(ab')2.

UNLABELLED: The clinical feasibility of radioimmunotherapy (RIAIT) was assessed in patients with metastatic, carcinoembryonic antigen (CEA)-producing cancers who had minimal residual or small-volume disease (tumor lesions < or = 3 cm in diameter). METHODS: Thirteen cancer patients (8 colorectal, 3 lung, 1 pancreatic and 1 medullary thyroid cancer) received RAIT with 131I-NP-4 F(ab')2 anti-CEA antibody. The radioactive dose given was based on a prescribed radiation dose to the red marrow. Ten of the 13 patients received initial therapeutic doses delivering 150-450 cGy to the red marrow (70-296 mCi) and six patients had more than one therapy infusion. RESULTS: Targeting of all known tumor lesions < 0.5 cm [corrected] in diameter was possible in nine patients and at least one tumor lesion was evident in all patients. Disease stabilization ranging from 3.5 to 7 mo was seen in 6 of the 13 patients who previously had clear evidence of progressive disease. Four of the six patients with disease stabilization received the presumed maximum tolerated dose of 450 cGy to the red marrow. Red marrow suppression was the only observed toxicity and there was a good correlation between the red marrow dose and myelotoxicity. Red marrow doses < or = 250 cGy resulted in < or = grade 2 myelotoxicity and a red marrow dose of 450 cGy resulted in reversible grade 3 or 4 myelotoxicity in 3 of 6 patients. Human anti-mouse antibodies (HAMA) developed in all but one of the six patients who received multiple therapeutic infusions of the antibody. CONCLUSION: RAIT of patients with small-volume disease is feasible and these patients should be considered for future dose-intensification trials because of their generally poor prognosis.

Adult↗
PubMed1996

Reduction of renal uptake of monoclonal antibody fragments by amino acid infusion.

UNLABELLED: The renal uptake of radiolabeled antibody fragments and peptides presents a problem in radioimmunodetection and therapy, compromising lesion sensitivity, especially with intracellularly-retained isotopes. Previously, we showed that cationic amino acids and their derivatives are capable of significantly reducing kidney uptake in animals. We report our initial clinical results of successful renal uptake reduction in five patients who underwent cancer radioimmunodetection with 99mTc-anti-CEA Fab' fragments. METHODS: The patients were infused with two liters of a commercially-available nutritive amino acid solution (containing approximately 2.25 g/liter lysine-glutamate and 2.50 g/liter arginine), whereas 75 control patients received the same volume of saline (quantification of organ and tumor kinetics from conjugate whole-body views by ROI technique). RESULTS: The renal uptake in the amino acid group was significantly lower (p<0.05) than in the control group (11.1 +/- 2.0% injected dose versus 17.7 +/- 7.0% injected dose at 24 hr postinjection), whereas the uptake of all other organs remained unaffected. Gel filtration chromatography of the urine taken from amino-acid-treated patients showed that a significantly higher amount of excreted activity was bound to intact Fab' (53% of excreted activity) in contrast to only less than 10% in the control group. CONCLUSION: The renal uptake of monoclonal antibody fragments in patients can be reduced significantly by amino acid infusion, even at considerably lower doses than those that were safe and effective in animals. As was found in animals, the mechanism seems to rely on an inhibition of the re-absorption of tubularly-filtered proteins by the proximal tubule cells. These results encourage further clinical trials to lower the renal uptake experienced in radioimmunodetection, as well as in therapeutic trials with antibody fragments and peptides.

Aged↗
PubMed1995

Site-specific modifications of light chain glycosylated antilymphoma (LL2) and anti-carcinoembryonic antigen (hImmu-14-N) antibody divalent f1agments.

Site-specific introduction of metal-chelating groups into F(ab')2 fragments of an antilymphoma antibody (LL2) possessing a natural Asn-linked light chain carbohydrate and an anti-carcinoembryonic antigen antibody (hImmu-14-N) grafted with a light chain carbohydrate site is described. For this purpose, four yttrium- (and indium)-chelating agents were used, containing a primary amino group for antibody binding and 1-(4-substituted benzyl)diethylenetriaminepentaacetic acid as the metal-chelator, separated by structurally different additional linkers. Conjugates were prepared by reacting excess chelator with oxidized carbohydrate of F(ab')2 fragments, with or without a subsequent reduction step. The conjugates, with up to an average of 5.5 chelating groups attached to a F(ab')2 fragment, were readily labeled with 90Y and 111In and were found to retain antigen-binding ability in in vitro assays. Tumor targeting was demonstrated using a 88Y-labeled hImmu-14-N F(ab')2 carbohydrate-modified conjugate. 2-Pyridyldithiopropionic hydrazide was conjugated to the carbohydrate region, and the disulfide was selectively deprotected to the thiol group, which is reactive with reduced 99mTc. These initial experiments establish that light chain carbohydrate modification of F(ab')2 is as facile as with the Fc-region carbohydrate of intact IgG, and thereby offer the possibility of designing site-specifically substituted F(ab')2 fragments with favorable pharmacokinetic properties.

Animals↗
PubMed1995

Improved staging of B-cell non-Hodgkin's lymphoma patients with 99mTc-labeled LL2 monoclonal antibody fragment.

Radioimmunodetection (RAID) with the 99mTc-labeled Fab' fragment of monoclonal antibody (MoAb) LL2 has been reported to have a high lesion detection rate for malignant lymph nodes as well as for visceral and skeletal tumor masses (20). Our purpose in this study was to evaluate the safety and staging efficacy of the 99mTc-labeled Fab' fragment of MoAb LL2 in patients with various grades and stages of B-cell non-Hodgkin's lymphoma (NHL). Thirty adult patients, 13 male and 17 female, ranging in age from 20 to 80 years, with at least one biopsy-proved malignant node (> or = 0.5 cm) and a Karnofsky performance score of > or = 60% were enrolled in this study. Patients underwent selected planar and single photon emission computed tomographic imaging at 6 and 18 h after receiving an i.v. infusion of 0.25-1 mg of LL2 Fab' fragment labeled with 25-30 mCi of 99mTc. RAID findings were compared with physical examination, chest radiography, computed tomography, magnetic resonance imaging, and bone and 67Ga scan findings. The RAID scan was positive in all but three patients. The sensitivity for known lesions was 90% and for suspected lesions, 89%, with an overall positive predictive value of 96%. Twenty-nine of the 30 patients had either low- or intermediate-grade NHL. Fifteen of 16 (94%) low-grade patients were correctly staged by RAID; three of these patients were correctly upstaged. Twelve of the 13 (92%) intermediate-grade patients were correctly staged by RAID; two of these patients were correctly upstaged. The high-grade NHL patient was staged correctly by RAID. Infused doses of 99mTc-labeled LL2 Fab' of 0.5 and 1.0 mg did not affect lesion sensitivity. The RAID sensitivity decreased as the total tumor burden increased > or = 100 g. On the basis of these initial results, the 99mTc-labeled Fab' fragment of MoAb LL2 (LymphoScan) seems to yield useful clinical information, especially for the staging of B-cell NHL patients who do not have bulky disease (i.e., tumor burdens of < or = 100 g).

Adult↗
PubMed1995

67Ga citrate versus 99mTc-labeled LL2-Fab' (anti-CD22) fragments in the staging of B-cell non-Hodgkin's lymphoma.

The value of 67Ga citrate scanning as a transferrin receptor agent was compared in this study with a 99mTc-labeled anti-CD22 (B-cell) Fab' fragment (LL2) in patients with low- and high-grade B-cell non-Hodgkin's lymphoma (NHL). Thirteen patients with histologically confirmed NHL were examined prospectively with both radiopharmaceuticals within 8 days. The results of immunoscintigraphy were compared with those of 67Ga scanning and the clinical and radiological workup (computed tomography, ultrasound, and magnetic resonance imaging) of the patients. The overall sensitivity of 67Ga citrate and 99mTc-labeled LL2 fragment was each 80% in a total of 43 lesions. Low-grade lymphoma patients had a higher sensitivity in LL2 imaging (82% versus 71%), and high-grade lymphoma patients in 67Ga citrate scanning (100% versus 75%). The target:background ratio in low-grade NHL for LL2 was 1.43 +/- 0.3:1 versus 1.8 +/- 0.5:1 in 67Ga scans; in high-grade NHL, 1.49 +/- 0.35:1 versus 2.2 +/- 0.8:1, respectively. Single-photon emission computed tomography imaging was necessary in 21.7% of the patients 4 h after injection to localize the lesions. In conclusion, the overall sensitivity of 99mTc-labeled LL2 is comparable to 67Ga citrate scanning in patients with B-cell NHL. 99mTc-labeled LL2 antibodies are rapid to use, are safe, and need a shorter imaging time (24 h versus 72 h). Because of these advantages, 99mTc-labeled LL2 may be superior to 67Ga scanning for the staging of lymphoma patients.

Adult↗
PubMed1995

Targeting of liver metastases of colorectal cancer with IgG, F(ab')2, and Fab' anti-carcinoembryonic antigen antibodies labeled with 99mTc: the role of metabolism and kinetics.

The aim of this study was to investigate targeting of the liver metastases by directly 99mTc-labeled complete (IgG) and fragmented antibodies [F(ab')2 and Fab'] in relation to their kinetics and metabolic fate. A total of 127 patients with metastatic colorectal cancer were examined [IgG1, BW 431/26 (Behringwerke, Marburg, Germany) n = 50; F(ab')2, F023C5 (Sorin Biomedica, Saluggia, Italy) n = 58; Fab', IMMU-4 (Immunomedics, Morris Plains, NJ) n = 19]. Native monoclonal antibodies (MAbs), serum samples from 10 min to 24 h postinjection (p.i.), and urine were analyzed by gel filtration chromatography. Kinetic data were deduced from whole-body and single-photon emission computed tomographic scans, performed 10 min to 24 h p.i. (region-of-interest technique). In BW 431/26, 96% of injected activity was labeled IgG1; in F023C5, 29% was F(ab')2, and 71% was Fab'; and in IMMU-4, 92% was Fab', and 8% was F(ab')2. Serum half-lives were: IgG1, 36 h (liver uptake predominant); F(ab')2, 16 h; and Fab', 4 h (renal uptake predominant). All MAbs were metabolized, fragments more rapidly than IgG, to low-molecular-weight products and excreted into the urine (e.g., Tc-cystine). In targeting liver metastases, sensitivities were found to be higher for fragments (44.1, 72.5, and 80% for BW 431/26, F023C5, and IMMU-4, respectively) but at significantly lower tumor:background ratios than with IgG (1.78 +/- 0.29 versus 1.29 +/- 0.11 and 1.43 +/- 0.53; P < 0.01). With IgG, there was a continuous tumor uptake over 24 h, whereas with fragments, the maximal uptake occurred mostly within 1 h, with subsequent clearance being slower for antigen-bound activity than for nonspecific background. Hence, diagnosis was possible mostly after 4 h with fragments but often not before 24 h with IgG. These results show that the higher sensitivity of fragments in liver lesion targeting at earlier p.i. times does not rely on an increased antibody uptake but on a more rapid clearance of nonspecific background activity due to faster metabolism and excretion. Intact MAbs show a slow, continuous uptake, leading to higher tumor:background ratios at later p.i. times, often beyond the imaging possibilities of 99mTc.

Carcinoembryonic Antigen↗
PubMed1995

Estimates of red marrow dose by sacral scintigraphy in radioimmunotherapy patients having non-Hodgkin's lymphoma and diffuse bone marrow uptake.

According to the recommendations of the Dosimetry Task Group of the American Association of Physicists in Medicine, blood-derived estimates of the red marrow (RM) dose from radiolabeled monoclonal antibodies (MAbs) are valid only if the RM is devoid of any specific uptake. There is, therefore, a clear need for an alternative method for estimating the RM dose in patients receiving MAbs that target normal or abnormal (malignant) bone marrow elements. Radiolabeled LL2, an anti-B-cell murine MAb, targets normal B cells and malignant lymphoma cells in the RM. This may result in an increased radiation dose to the RM through neighboring targeted activity. We investigated whether imaging-based estimates of the RM dose, particularly using sacral scintigraphy, correlate with myelotoxicity in non-Hodgkin's lymphoma patients who received 131I-LL2. The sacrum-based RM dose (RMs) was estimated from sacral activity by assuming that 9.9% of the total adult RM is contained in the sacrum. The sacrum was not used if there was focally increased or decreased sacral uptake. Myelotoxicity was assessed based on Radiation Therapy Oncology Group criteria. Twelve of 21 non-Hodgkin's lymphoma patients treated had adequate imaging, dosimetry, and follow-up to evaluate myelotoxicity. Eight of these patients had diffusely increased RM uptake on their MAb scans. The average estimated RMs in the eight patients was 168 +/- 62 cGy (mean +/- SD) with only 50 mCi 131I-LL2. Six of these patients (75%) developed grade 3 or 4 myelotoxicity. In contrast, the average RMs in the four patients who did not have any enhanced uptake on their scans was 71 +/- 30 cGy (P < 0.02). None of these patients developed grade 3 or 4 toxicity. These results suggest that image-based estimates of the RM dose may be predictive of myelotoxicity and should be used in patients with diffuse RM uptake on their scans.

Antibodies, Monoclonal↗
PubMed1995

In vitro and in vivo reactivity of an internalizing antibody, RS7, with human breast cancer.

RS7, a murine IgG1 antibody raised against human lung carcinoma, possesses pancarcinoma reactivity. The antigen defined by this antibody is present in tumors of the lung, stomach, bladder, breast, ovary, uterus, and prostate. Efficient targeting and therapy by radiolabeled RS7 has been demonstrated previously in animals bearing Calu-3 (an adenocarcinoma of the lung) xenografts. In this study, the efficiency of tumor targeting and the efficacy of therapy of this antibody in nude mice bearing the MDA-MB-468 human breast carcinoma were evaluated. The tumor:nontumor ratios of RS7 were 1.9-2.1 times higher than those for Ag8 (the control antibody) on day 14, except for the heart. These values were similar to that of RS7 in the Calu-3 xenograft model. Radioimmunotherapy using 250 microCi of 131I-labeled RS7 in animals bearing approximately 0.1 cm3 tumors (approximately 10 days old) caused the disappearance of tumors in 6 of 10 animals at 2 weeks postinjection. Tumors eventually disappeared from all animals, and animals remained tumor-free until the termination of the study (11 weeks of duration), except for one animal that developed a transient reappearance of tumor. The tumors in animals that received an equal dose of 131I-labeled Ag8, or unlabeled RS7 or Ag8, either were unchanged or continued to grow. Treatment that used 275 microCi of 131I-labeled RS7 in animals carrying established tumors (1 month old, approximately 0.2-0.3 cm3) showed that this antibody is effective in controlling the growth of this tumor. Tumors in the treatment group began to disappear between the second and third weeks after the injection of the radiolabeled antibody. Seven of 10 animals remained tumor free at 15 weeks after the injection. Tumors in animals that received an equal dose of control antibody persisted but grew at a slower pace compared to the untreated group. No systemic toxicity was observed.

Adenocarcinoma↗
PubMed1995

Targeting and initial radioimmunotherapy of medullary thyroid carcinoma with 131I-labeled monoclonal antibodies to carcinoembryonic antigen.

The targeting potential of 131I-labeled NP-4 and MN-14 anti-CEA (carcinoembryonic antigen) monoclonal antibodies (MAbs) was assessed in 19 patients with metastatic medullary thyroid cancer (MTC). Seventeen of these patients also entered pilot radioimmunotherapy studies with nonmyeloablative doses of 131I-anti-CEA MAbs. Tumor targeting was possible in all 19 patients, with an overall lesion sensitivity of 91%. Tumor dosimetry with 131I-MN-14 IgG or F(ab)2 was very favorable, with tumor doses of 14.3 +/- 8.3 cGy/mCi and tumor:red marrow dose ratios exceeding 3:1 for most lesions. Limited antitumor effects lasting up to 26+ months, based on physical exam, tumor markers, computed tomography, or a followup MAb scan, were seen in 5 of 11 assessable patients given relatively low doses of 131I-labeled anti-CEA MAbs. We conclude that anti-CEA MAbs are excellent agents for targeting metastatic MTC. The high tumor uptake of the 131I-anti-CEA antibodies and evidence of tumor response in some patients suggest that radioimmunotherapy with radioiodinated anti-CEA MAbs may be an effective treatment for MTC, particularly when the maximum tolerated dose is given alone or in combination with autologous red marrow or peripheral stem cell support.

Animals↗