Endobronchial administration of iodine-131 B72.3 monoclonal antibody in patients with lung cancer

We tested the feasibility of endobronchial administration of radiolabelled monoclonal antibodies (MoAbs) and the biodistribution of the radiotracer. Ten patients with histological confirmed adenocarcinoma or squamous cell carcinoma were studied. Nine received 470 Ci (103 g) of Iodine-131-B72.3, a monoclonal antibody reacting against TAG 72 antigen, while one patient received 502 Ci (291 g) of ¹³¹I-4C4, an indifferent antibody used for comparison in a negative control study. The radiolabelled antibody was administered through a flexible fiberoptic bronchoscope and placed on the tumour mass under visual monitoring. Scans with a large field-of-view gamma-camera showed retention of ¹³¹I-B72.3 at the tumour site up to 6–9 days in six of eight patients. No other organs were visualized with the exception of faint activity in the gastrointestinal tract, bladder and thyroid. On the contrary, the indifferent antibody ¹³¹I-4C4 was not retained at the tumour site 6 days after MoAb administration, and more prominent activity was found in the gastrointestinal tract. In one patient the study was not technically adequate because of failure of the delivery system. The vascular compartment contained less than 3% of the administered dose. We conclude that endobronchial administration is a feasible technique and allows stable and specific targetting of bronchial tumours. Furthermore, the low activity found in the plasma and other organs suggests that this approach may be used to deliver therapeutic doses of MoAbs to lung cancers.Preliminary results were presented at the European Nuclear Medicine Congress, August 29-September 2, 1988, Milan, Italy. Offprint request to: S. Del Vecchio     

Endobronchial administration of iodine-131 B72.3 monoclonal antibody in patients with lung cancer

We tested the feasibility of endobronchial administration of radiolabelled monoclonal antibodies (MoAbs) and the biodistribution of the radiotracer. Ten patients with histological confirmed adenocarcinoma or squamous cell carcinoma were studied. Nine received 470 muCi (103 micrograms) of Iodine-131-B72.3, a monoclonal antibody reacting against TAG 72 antigen, while one patient received 502 muCi (291 micrograms) of 131I-4C4, an indifferent antibody used for comparison in a negative control study. The radiolabelled antibody was administered through a flexible fiberoptic bronchoscope and placed on the tumour mass under visual monitoring. Scans with a large field-of-view gamma-camera showed retention of 131I-B72.3 at the tumour site up to 6-9 days in six of eight patients. No other organs were visualized with the exception of faint activity in the gastrointestinal tract, bladder and thyroid. On the contrary, the indifferent antibody 131I-4C4 was not retained at the tumour site 6 days after MoAb administration, and more prominent activity was found in the gastrointestinal tract. In one patient the study was not technically adequate because of failure of the delivery system. The vascular compartment contained less than 3% of the administered dose. We conclude that endobronchial administration is a feasible technique and allows stable and specific targetting of bronchial tumours. Furthermore, the low activity found in the plasma and other organs suggests that this approach may be used to deliver therapeutic doses of MoAbs to lung cancers.     

Radioimmunoscintigraphy of colon cancer with iodine-131-labeled B72.3 monoclonal antibody

The monoclonal antibody B72.3 is a murine IgG1 that is reactive with a wide range of carcinomas while demonstrating little or no reactivity to normal adult tissues. We have shown (27) quantitative analyses demonstrating selective targeting of [131I]B72.3 IgG to metastatic colorectal cancer. We have also shown (28) that (a) B72.3 localization in metastases correlated with the percentage of tumor cells in the biopsy specimen; (b) B72.3 could localize in carcinomas of various degrees of differentiation with best localization in well-differentiated tumors and (c) [131I]B72.3 could penetrate tumor masses, as determined by autoradiographic studies. We report here the various parameters effecting radioimmunoscintigraphy with [131I]B72.3 IgG. Sixteen of 35 patients with colorectal carcinoma had positive scans (without blood-pool subtraction). High circulating TAG-72 antigen levels correlated with positive scans. No dose dependent differences were seen in biodistribution or tumor imaging. The plasma clearance and urinary excretion of [131I]B72.3 and [125I]BL-3 (nonspecific control) were not significantly different. No toxicity was noted. Approximately one-half of patients developed human anti-mouse immune response.     

Evaluation of therapeutic response using iodine-131-B72.3 monoclonal antibody in patients with ovarian carcinoma

We used radiolabelled monoclonal antibodies (MoAbs) to prove disease persistence after treatment for ovarian carcinoma. Twelve patients with histologically confirmed ovarian carcinoma were studied. They received 5 mCi (1 mg) of iodine-131-B72.3 by intravenous injection before and after a complete course of chemotherapy. Images were obtained with a LFOV gamma camera 2 h after MoAb administration and daily up to 6 days. Before treatment 8 patients had a true positive scan. Questionable antibody uptake was observed in 2 patients while 1 had a true negative scan and 1 a false-negative examination. After treatment the therapeutic response was evaluated. Five patients had partial remission and antibody scan showed persistence of disease in all patients except 1. Four patients showed progression of the disease and 1 no change. The antibody scan was positive in 4 and questionable in 1. Two patients had complete remission and negative antibody scans. Computed tomography (CT) could not always discriminate postoperative fibrosis from tumour lesions, especially when the peritoneum was involved in the disease. High serum levels of tumour markers were constantly associated with the presence of tumour lesions, but normal values did not guarantee absence of disease. We conclude than the antibody scan is complementary to CT and serum tumor markers in the definition of therapeutic response.Preliminary results were presented at the 2nd International Conference on Diagnosis and Therapy with Monoclonal Antibodies, Naples, Italy, 26–28 April 1990     

Evaluation of therapeutic response using iodine-131-B72.3 monoclonal antibody in patients with ovarian carcinoma

We used radiolabelled monoclonal antibodies (MoAbs) to prove disease persistence after treatment for ovarian carcinoma. Twelve patients with histologically confirmed ovarian carcinoma were studied. They received 5 mCi (1 mg) of iodine-131-B72.3 by intravenous injection before and after a complete course of chemotherapy. Images were obtained with a LFOV gamma camera 2 h after MoAb administration and daily up to 6 days. Before treatment 8 patients had a true positive scan. Questionable antibody uptake was observed in 2 patients while 1 had a true negative scan and 1 a false-negative examination. After treatment the therapeutic response was evaluated. Five patients had partial remission and antibody scan showed persistence of disease in all patients except 1. Four patients showed progression of the disease and 1 no change. The antibody scan was positive in 4 and questionable in 1. Two patients had complete remission and negative antibody scans. Computed tomography (CT) could not always discriminate postoperative fibrosis from tumour lesions, especially when the peritoneum was involved in the disease. High serum levels of tumour markers were constantly associated with the presence of tumour lesions, but normal values did not guarantee absence of disease. We conclude than the antibody scan is complementary to CT and serum tumor markers in the definition of therapeutic response.     

Differences in biodistribution of indium-111-and iodine-131-labeled B72.3 monoclonal antibodies in patients with colorectal cancer

We have compared the biodistributions of [131I]B72.3 and 111In-SCN-Bz-DTPA B72.3 monoclonal antibody (MoAb) in patients with metastatic colon cancers. B72.3 is an IgG1 that recognizes a mucin-like colon cancer associated antigen. Eight patients were infused with 3-5 mCi and 0.36-20 mg of 111In-labeled B72.3 prepared with a bifunctional chelate, isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA). The biodistribution was compared with that of 13 patients previously studied as part of a separate trial, with 1-10 mCi and 0.16-1.35 mg of [131I]B72.3. The Beta T1/2 in serum was 63 +/- 5 hr for 111In-SCN-Bz-DTPA B72.3 and 52 +/- 10 hr for [131I]B72.3. Whole-body retention of the 111In (T1/2 = 11.8 days) was significantly longer than for [131I]B72.3 (T1/2 = 3.3 days), p less than 0.000001. The 131I was excreted primarily through the urine. Urinary excretion of 111In was low and gamma camera images confirmed that some 111In was excreted in the bowel. Tumor localization was seen in one of seven evaluable patients receiving 111In-SCN-Bz-DTPA B72.3. Gamma camera images showed that the liver concentrates 111In but not 131I. We conclude that 111In-SCN-Bz-DTPA B72.3 is metabolized in a different manner from the iodinated B72.3. The high concentration and prolonged retention of 111In by the liver interferes with tumor imaging of metastases.     

Peritoneal carcinomatosis: imaging with intraperitoneal injection of I- 131-labeled B72.3 monoclonal antibody

Monoclonal antibody (MoAb) B72.3 is reactive with a variety of carcinomas such as colorectal and ovarian carcinoma and not reactive with a range of normal tissues in adults. Twelve patients, ranging in age from 16 to 63 years, with metastatic colorectal or appendiceal carcinoma were studied by means of radioimmunoscintigraphy after injection of 5-10 mCi (185-370 MBq) of iodine-131-labeled B72.3 immunoglobulin G (IgG). Eight of the 12 patients had positive scans. In three of these patients the MoAb scan depicted tumors that were not found by other means. Positive scans had excellent correlation with surgical findings in seven patients and caused underestimation of the extent of disease in one patient. In one patient the scan was technically inadequate and could not be evaluated. In three patients the scan was negative. No adverse reactions were associated with the infusions.     

In vivo fate of monoclonal antibody B72.3 in patients with colorectal cancer

Radiolabeled B72.3 (anti-TAG-72) has been shown to selectively localize metastatic lesions in 70%-80% of the cases. Serum samples from 27 colorectal carcinoma patients who received iodine-131-(131I) B72.3 by i.v. administration were analyzed. Circulating immunoreactive antibody followed a biphasic clearance pattern. High-performance liquid chromatography (HPLC) and SDS-polyacrylamide gel electrophoresis demonstrated that 131I-B72.3 retained its integrity in the patients' sera. HPLC analysis also demonstrated the presence of immune complexes in the sera of 12 patients; this correlated with elevated levels of circulating TAG-72. Several different HAMA response patterns were detected in the 25 patients' sera that were analyzed; some patients developed HAMA as early as 5-7 days post-MAb injection. Higher doses of administered MAb B72.3 correlated with the development of HAMA (p = 0.007). The presence of elevated levels of TAG-72 in the patients' pre-inoculum serum was shown to correlate with the detection of lesions by gamma scanning. Serum TAG-72 may serve as a criteria for patient selection for immunodiagnostic or immunotherapeutic procedures using MAb B72.3.     

Absorbed dose estimates for 131I-labelled monoclonal antibody therapy in patients with intraperitoneal pseudomyxoma

Seven patients with intraperitoneal pseudomyxoma originating from the appendix (4 cases) and from the ovary (3 cases) were treated with radioimmunotherapy. During the therapy, nine infusions of 3.0-4.2 GBq of 131I-labelled B72.3 monoclonal antibody were administered. We developed three-dimensional dose calculation software that can utilize activity maps based on SPET images to calculate the absorbed dose distribution using point source kernels. The dose calculation program was employed to calculate absorbed doses to various organs. The calculated dose distributions enable us to evaluate the variation in dose within the organs, which is normally not available using approaches based on geometric models. The patient-specific absorbed dose calculations were compared with doses based on a model that uses photon S-factors derived from a standard phantom. The compared doses agreed well on average, but in some organs showed large discrepancies.     

A prospective imaging study of 131I-B72.3 monoclonal antibody in patients with epithelial ovarian cancer: preliminary report

Twenty patients with known ovarian cancer have been investigated in this pilot study to verify the clinical usefulness of radioimaging using the B72.3 monoclonal antibody labelled with iodine-131. No adverse reactions occurred after intravenous injection of B72.3 MoAb. The radioimaging results were compared with those obtained with other diagnostic methods, including computed X-ray tomography and ultrasound. A sensitivity of 85% in the detection of primary ovarian cancers and collections of ascites, and of 84% in the detection of abdominal and extraperitoneal metastases has been demonstrated using this radioiodinated antibody in vivo. No false localization occurred. Immunohistochemical studies showed no cross-reactions between B72.3 MoAb and mesothelial cells, confirming the high specificity of binding between B72.3 MoAb and neoplastic cells in ascites. Negligible uptake of radiolabelled B72.3 MoAb has been demonstrated in the unaffected ovary. The major advantage of using this monoclonal antibody is related to the expression of a recognized antigen (called TAG 72) in mucinous, serous and in differentiated adenocarcinomas of the ovary.     

Pharmacokinetics of indium-111-labeled B72.3 monoclonal antibody in colorectal cancer patients.

Mean time parameters provide a new approach to plasma pharmacokinetics of radiolabeled Mabs that may show important patient differences affecting diagnosis or treatment. We determined mean time pharmacokinetic parameters for 11 patients entered in a Phase I/II clinical trial for detection of colorectal cancer. Patients were administered 0.5-2 mg of B72.3 anti-TAG-72 radiolabeled with 3.5-5 mCi of 111In, plasma activity was measured over time. Mean time pharmacokinetic parameters were (mean +/- s.e.m.): mean residence time; body (MRTB) 88.9 +/- 7.2 hr, central (MRTC) 73.8 +/- 6.0 hr; mean transit time, central (MTTC) 41.1 +/- 9.0 hr; mean residence time, periphery (MRTP) 15.1 +/- 3.4 hr; intrinsic mean residence time, periphery (IMPTP) 39.0 +/- 7.6 hr; mean transit time, periphery (MTTP) 24.0 +/- 6.7 hr; probability of distribution (PRD) 50% +/- 10%; and n compartmental cycles of 4.54 +/- 2.3 times. In patients with increased circulating specific TAG-72 antigen, MRTC greater than MTTC and n much greater than 1. In patients without specific antigen, MRTC approximately equal to MTTC and n much less than 1. Pharmacokinetic studies may identify patients who do not have the tumor produced target antigen for the specific Mab and may provide an opportunity to select another specific Mab with an increased chance for successful diagnosis or treatment.     

Radioimmunoscintigraphy of human colon cancer xenografts in mice with radioiodinated monoclonal antibody B72.3

Monoclonal antibody B72.3 reacts with a tumor-associated antigen that is found on human breast and colon carcinomas in significantly higher concentration than in normal adult tissues. Intact B72.3 IgG was labeled with I-131 or I-125 and injected into athymic mice bearing xenografts of human colon cancer. Whole-body scintiphotos obtained with a pinhole collimator demonstrated tumor localization within 24 hr after intravenous administration, and the tumor-to-background ratio rose continuously for at least 14 days. Progressive antibody accumulation was observed in the tumor during the first 3 days, but no significant normal organ localization was observed at any time. No localization was seen in control tumors, a human melanoma xenograft that lacks the antigen recognized by B72.3. The pharmacokinetics of this antibody in tumor-bearing mice suggest that I-131 B72.3 may be useful for radioimmunotherapy as well as radioimmunoscintigraphy of colon cancer in man.     

Radioimmunotherapy with intravenously administered 131I-labeled chimeric monoclonal antibody MOv18 in patients with ovarian cancer.

We investigated the safety and pharmacokinetics of (131)I-labeled chimeric monoclonal antibody MOv18 ((131)I-c-MOv18 IgG) in patients with ovarian cancer and the estimated radiation dose to cancer-free organs and tumor. METHODS: Three patients were injected intravenously with 3 GBq (131)I-c-MOv18. Toxicity was evaluated according to the World Health Organization toxicity scales. Blood sampling was performed for 12 wk after injection. Whole-body and SPECT imaging was performed frequently. Dose rates were obtained with a portable dose-rate measure. Quantitative activity analysis of several organs was performed with the region-of-interest technique. Absorbed doses were calculated using MIRDOSE3. RESULTS: Transient changes in hematologic profiles were seen in 2 patients. Pancytopenia developed in 1 patient; on analysis, she entered the study probably with exhausted bone marrow reserves. Nonhematologic toxicity was mild. No human antichimeric antibody responses were observed. Mean isolation time was 12 d. The plasma elimination half-life increased almost 3-fold compared with that after tracer doses of c-MOv18. Dosimetry showed mean absorbed doses of 163, 380, 276, 338, 781, and 216 cGy, for whole-body, liver, kidney, spleen, lung, and red marrow, respectively. Tumor-absorbed doses ranged from 600 to 3800 cGy. All patients achieved a stable disease state, as confirmed by CT and carcinoma-associated antigen CA 125, lasting from 2 to >6 mo. CONCLUSION: (131)I-labeled c-MOv18 can safely be given to patients with noncompromised bone marrow reserves and may have therapeutic potential particularly in patients with minimal residual disease.     

Phase I trial of iodine-131-chimeric B72.3 (human IgG4) in metastatic colorectal cancer.

Twelve patients with metastatic colorectal cancer participated in a Phase I trial of 131I-labeled chimeric B72.3 (human IgG4). Consecutive groups of patients received 18 mCi/m2, 27 mCi/m2 and 36 mCi/m2. No acute side effects related to antibody administration were noted. Bone marrow suppression was the only side effect; it was dose-dependent and correlated with whole-body radiation dose estimates. The lowest dose level produced no marrow suppression, whereas 27 mCi/m2 resulted in Grade 1 and 2 marrow suppression in two of three patients. The maximum tolerated dose was 36 mCi/m2 with all six patients at this dose level having at least Grade 1 and two patients with Grade 3 and 4 marrow suppression. Eight of 12 patients had radioimmune imaging of tumor sites at 5-22 days. Seven patients had an antibody response to initial infusion. On retreatment, whole-body kinetics and imaging were altered for patients with a high anti-ch-B72.3 response. Thus, chimeric B72.3 (IgG4) has limited utility as a means of delivering multiple therapeutic doses of 131I in the majority of patients; alternative strategies including second generation anti-TAG-72 monoclonal antibodies, other radioisotopes and other chimeric human isotypes will need to be pursued.     

Pharmacokinetic evaluation of technetium-99-metallothionein-conjugated mouse monoclonal antibody B72.3 in rhesus monkeys

These studies were conducted to determine the biodistribution and pharmacokinetics of [99mTc]metallothionein-conjugated B72.3 ([ Tc]MT-B72.3) in Rhesus monkeys (Macaca mulatta) that were performed as part of the preclinical evaluation of [Tc]MT-B72.3. The B72.3-MT conjugate was studied at three doses of B72.3 ranging from 0.03 mg/kg to 1 mg/kg to determine whether a relationship existed between the dose of total antibody administered intravenously and the biodistribution and clearance of the radiolabeled protein. Results indicated that [Tc]MT-B72.3 distributes rapidly to central body cavity organs and that there was no difference in the rate of blood elimination for the three doses of B72.3 studied. The terminal phase of blood elimination was found to be 26.2 +/- 6.1 hr for the combined groups of monkeys. Approximately one-half of injected 99mTc activity was recovered in the urine within 24 hr. A second purpose of these studies was to evaluate the overall immunogenicity of the mouse monoclonal B72.3 IgG1 antibody in Rhesus monkeys. These results demonstrated that a single i.v. exposure to mouse monoclonal B72.3 at doses of 0.3 mg/kg or greater elicited antibody production to B72.3 in Rhesus monkeys within 3 wk. Analysis of [Tc]MT-B72.3 biodistribution and clearance in monkeys with circulating levels of antibodies to B72.3 (immunized monkeys) revealed that the liver was the primary site of clearance of the presumed immune complex and that blood elimination was greatly accelerated.     

Radioimmunotherapy of patients with cutaneous T-cell lymphoma using an iodine-131-labeled monoclonal antibody: analysis of retreatment following plasmapheresis

Radioimmunotherapy retreatment of patients receiving radiolabeled murine monoclonal antibodies is difficult because of human antimurine antibody (HAMA) formation. Retreatment therapy was initiated in three patients at the time of disease progression using a radioiodinated monoclonal antibody (T101). The clinical protocol consisted of a two day plasma exchange (4-6 L) to reduce HAMA titers. Immunoimaging was performed with 5 mCi 131I-T101 (10 mg). Gamma scintillation images were obtained 18 hr postinfusion, and radiation dosimetry estimates were performed. At 24 hr postinfusion, each patient received a 100-mCi 131I-T101 (10 mg) therapy dose. Results obtained after plasmapheresis showed a significant reduction, ranging from 28%-61%, in HAMA titers. Blood clearances were markedly different between initial therapy and retreatment therapy for patient with high HAMA titers, reflecting immune complex formation. Two patients responded to retreatment therapy with responses lasting 1 to 2 mo. Minimal acute and no chronic toxicities were observed during the retreatment protocol.     

Radiation dose rates from patients receiving iodine-131 therapy for carcinoma of the thyroid

Patients treated with radioiodine present a radiation hazard and precautions are necessary to limit the radiation dose to family members, nursing staff and members of the public. The precautions advised are usually based on instantaneous dose rates or iodine retention and do not take into account the time spent in close proximity with a patient. We have combined whole-body dose rate measurements taken from 86 thyroid cancer patients after radioiodine administration with published data on nursing and social contact times to calculate the cumulative dose that may be received by an individual in contact with a patient. These dose estimates have been used to calculate restrictions to patients' behaviour to limit received doses to less than 1 mSv. We have also measured urinary iodide excretion in 19 patients to estimate the potential risk from the discharge of radioiodide into the domestic drainage system. The dose rate decay was biexponential for patients receiving radioiodine to ablate the thyroid after surgery (the ablation group, A) and monoexponential for these receiving subsequent treatments for residual or recurrent disease (the follow-up group, FU). The faster clearance in the follow-up patients generally resulted in less stringent restrictions than those advised for ablation patients. For typical activities of 1850 MBq for the ablation patients and 3700 MBq or 7400 MBq for the follow-up patients, the following restrictions were advised. Patients could travel in a private car for up to 8 h on the day of treatment (for an administered activity of 1850 MBq in group A) or 4 and 2 h (for activities of 3700 or 7400 MBq in group FU) respectively. Patients should remain off work for 3 days (1850 MBq/group A) or 2 days (up to 7400 MBq/group FU). Partners should avoid close contact and sleep apart for 16 days (1850 MBq/group A) or 4–5 days (3700 or 7400 MBq/group FU). Contact with children should be restricted according to their age, ranging from 16 days (1850 MBq/group A) or 4–5 days (3700 or 7400 MBq in group FU) for younger children, down to 10 days (1850 MBq/group A) or 4 days (up to 7400 MBq/group FU) for older children. The cumulative dose to nursing staff for the week after treatment was dependent on patient mobility and was estimated at 0.08 mSv for a self-caring patient to 6.3 mSv for a totally helpless patient (1840 MBq/group A). Corresponding doses to nurses looking after patients in group FU were 0.18–12.3 mSv (3700 MBq) or 0.36–24.6 mSv (7400 MBq). Sensible guidelines can be derived to limit the dose received by members of the public and staff who may come into contact with cancer patient treated with radioiodine to less than 1 mSv. The rapid clearance of radioiodine in patients treated on one or more than one occasion means that therapy could be administered at home to selected patients with suitable domestic circumstances. In most cases the restriction times, despite the high administered activities, are less than those for patients treated for thyrotoxicosis. The concentration of radioiodide in domestic drainage systems should not pose a significant risk.