Scintigraphy with In-111-labeled monoclonal antitumor antibodies: kinetics, biodistribution, and tumor detection

The purpose of this study was to evaluate and compare the kinetics, biodistribution, and tumor-depicting properties of three intact indium-111-labeled murine monoclonal antibodies (MoAb) and to determine if use of In-111-labeled F(ab')2 fragments of one of them had advantages over its intact counterpart for immunoscintigraphy. Ten patients with prostate cancer were studied with an anti-prostatic acid phosphatase MoAb (PAY-276), with a resultant tumor detection rate of 15%. Twenty-eight patients with melanoma were studied with ZME-018, a MoAb that targets the KD-240 melanoma antigen. Forty-three percent of the known lesions were detected. Forty patients with carcinoembryonic antigen (CEA)-producing tumors were studied, 24 with intact ZCE-025, and anti-CEA MoAb, and 16 with its F(ab')2 fragment. With use of intact ZCE-025, 34% of known lesions were detected versus 83% with its F(ab')2 fragment. The distribution of each MoAb appears unique unto itself with regard to kinetics, normal tissue distribution, and response to MoAb mass.     

Intraperitoneal 131I- and 111In-791T/36 monoclonal antibody in recurrent ovarian cancer: imaging and biodistribution

An examination of the biokinetics and biodistribution of i.p. administered 131I- or 111In-labelled 791T/36 antibody (1 mg) has been carried out in five patients with stage III/IV ovarian cancer. Blood kinetics and urinary excretion of the radiolabels were assayed. Scintigraphy was performed immediately following administration and before and after peritoneal lavage at 48 h. Blood levels of both preparations rose over the first 20-40 h reaching 8-14% of the administered dose in the circulation and then declined (T1/2 of 40 h). Circulating radiolabel was still attached partially to antibody as shown by precipitation with anti-mouse IgG antiserum. The rapid appearance of radiolabel in the bloodstream meant that any tumour localization could be from circulating antibody rather than local infiltration. Interpretation of the images was difficult and the distribution of the tracer was different from that previously observed using i.v. administration of antibody. In some cases the images were confusing and the uptake of activity did not fit in with the clinical knowledge of the disease or the findings from laparoscopy. Tumour specimens resected at 4-5 days showed up to 0.02% of the dose g-1.     

In-111-labeled liposomes: dosimetry and tumor depiction

Neutral phospholipid vesicles (liposomes) were loaded with 0.5 mCi (18.5 MBq) indium-111 and administered to 24 patients with various types of cancer. The median diameter of the liposomes was 77 nm, and lipid dose was 0.78-6.25 mg/kg. Scans obtained 24 and 48 hours after injection of In-111 liposomes showed gradual blood clearance with homogeneous uptake in the normal liver and spleen. Dosimetric estimates for these organs were 2.3 +/- 1.1 and 2.3 +/- 1.4 rad (.02 +/- .01 Gy), respectively, with a whole-body estimate of 0.28 rad (.003 Gy). Radiation dose did not correlate with lipid dose. Total renal excretion of In-111 was less than 2% of the injected dose in all but two patients. Transient eosinophilia occurred in two patients. Tumor was seen in the scans of 22 of 24 patients (unbinded readings). In-111-labeled liposomes may enable the demonstration of suspected or unsuspected sites of tumor.     

Deep vein thrombosis: scintigraphic diagnosis with In-111-labeled monoclonal antifibrin antibodies

Fifty-two patients suspected of having deep vein thrombosis under-went scintigraphy with an indium-111-labeled monoclonal antifibrin antibody. Venography disclosed deep vein thrombosis in 31 patients. With the whole limb considered an anatomic entity, antifibrin antibody scintigrams obtained 2 hours after injection had a specificity and sensitivity of 81% and 84%, respectively. A higher sensitivity (92%) was found for a subgroup of patients (n = 44) with symptoms for less than 10 days. Regional sensitivities for all patients and for the subgroup, respectively, were 92% and 100% in the calf, 82% and 94% in the popliteal region, 63% and 71% in the thigh, and only 18% and 13% in the pelvis. Additional imaging performed 6 hours and 21 hours after injection in 12 patients and quantitative analysis done from scintigrams with and without blood-pool (technetium-99m human serum albumin) correction did not improve sensitivity. In-111-antifibrin antibody scintigraphy is an accurate method for diagnosis of acute established deep vein thrombosis of the calf and popliteal region; its sensitivity in the thigh is lower, and it is not feasible for diagnosis in the pelvic area.     

Radioimmunoimaging of malignant melanoma with In-111-labeled monoclonal antibodies 96.5 and ZME 018

This paper includes the results of imaging and kinetic studies on two kinds of In-111-labeled monoclonal antibodies (MoAbs), 96.5 and ZME 018, which are known to have capability of recognizing different surface antigens present in malignant melanoma cells. These MoAbs were supplied by Hybritech Inc. through Teijin Ltd. The former MoAb (96.5) was used on 11 cases of malignant melanoma and one case of basal cell carcinoma, and the latter MoAb (ZME 018) was used on 6 cases of malignant melanoma and one case of basal cell carcinoma. As for the malignant melanoma, the results obtained from both patients groups were compared to each other. Twenty-four out of 31 lesions in the former group and 9 (including 2 occult lesions) out of 10 lesions in the latter group were visualized. However, these positive ratios can not be compared to each other because of the very small number of the lesions in the latter group. One basal cell carcinoma each from both groups were faintly visualized. Distribution patterns of these In-111-labeled MoAbs were similar to each other. Except for the first two cases in the former group, labeling efficiencies were 94.3 +/- 0.7% with 96.5 and 92.0 +/- 0.6% with ZME 018. Urinary excretions on the 1st day were 8.3 +/- 0.9% with the former and 9.3 +/- 0.3% with the latter. However, there was no statistical difference. Following the 1st day, these values changed at the level of several per cent from the 2nd to 4th day, showing a subtle and gradual rise and slightly lower values for In-111-ZME 018. But, again, there were no statistical differences. Whole body retention curves in both groups were similar to each other, and blood clearance curves were also found similar in both groups. HAMA titers were checked in all patients and were found elevated after the administration in most of the cases. Although the number of patients tested in this series is small, especially with In-111-ZME 018, both MoAbs labeled with In-111 seem to be equally capable of visualizing malignant melanoma. Possibility of the treatment of malignant melanoma with this kind of technique was also discussed.     

Detection of pulmonary metastases in a patient with synovial cell sarcoma using In-111 labeled monoclonal antibody 19-24

A 35-year-old man was diagnosed in 1984 as having a synovial cell sarcoma of his right wrist without evidence of metastatic spread. The patient underwent regional hyperthermic chemoperfusion, wide-field excision, post-operative radiation therapy and systemic adjuvant chemotherapy. In 1986 and in 1987, because of new lesions found on chest radiographs, the patient underwent bilateral staging thoracotomies with resection of pulmonary metastases, followed by chemotherapy and radiotherapy. Later in 1987, a chest radiograph showed a large left hilar mass and multiple bilateral pulmonary nodules. Computerized tomography of the chest demonstrated a left hilar mass and two nodules in the right lower lung, raising the possibility of recurrent pulmonary metastatic cancer. As a diagnostic procedure, In-111 labeled monoclonal antibody (Mab) 19-24, produced against a human malignant fibrous histiocytoma, was infused intravenously, and 48-hour images revealed focal areas of increased uptake corresponding to the lesions seen on CT. At surgery, the lesions were confirmed to be synovial cell sarcoma. Imaging with Mabs specific for sarcoma may be particularly useful in sarcoma patients in whom there is clinical uncertainty regarding the nature of pulmonary lesions. In this case, the Mab was useful in distinguishing tumor deposits from postsurgical scarring and helped to guide subsequent surgery and treatment.     

In-111 labeled leukocytes: a review of problems in image interpretation

Leukocyte suspensions labeled with In-111 oxine or tropolone were administered intravenously to 150 patients for the detection of suspected foci of bacterial infection by gamma camera imaging. The results were correlated with other imaging modalities, and clinical, laboratory, and surgical findings after a minimum follow-up period of six months. Twenty-five of 29 foci of bacterial infection were demonstrated on the leukocyte-labeled images (sensitivity of detection = 86%). Three of the four missed lesions were chronic active osteomyelitis. The specificity of detection proved difficult to define, varying with different criteria for a false positive diagnosis. In every region of the body, a variety of lesions other than foci of bacterial infection produced positive uptake of the labeled leukocytes. An intense focal uptake was uncommon in lesions other than abscesses and hematomas. It was concluded that imaging with labeled leukocytes is valuable for demonstrating sites of infection in conjunction with other diagnostic methods. Detectable leukocytic infiltration, however, may occur in inflammatory lesions of any cause and in some noninflammatory states as well.     

Radioimmunodetection of lung cancer with IMACIS-1, I-131 labeled monoclonal antibodies to CEA and CA19-9

IMACIS-1 is a radiopharmaceutical containing a mixture of Iodine-131 labeled monoclonal antibodies to CEA and CA19-9. IMACIS-1 immunoscintigraphy was evaluated for tumor detection in 7 primary lung cancer and 2 metastatic lung cancer patients who received radiotherapy. No adverse side effects due to IMACIS-1 were observed in this study. Positive detection was achieved in 5 of 9 patients (55.6%). It was less, but nearly the same as the detection rate obtained with Gallium-67 citrate (⁶⁷Ga-citrate) in these patients. There was no clear correlation between IMACIS-1 accumulation and the CEA or CA19-9 serum levels. The IMACIS-1 positive detection rate decreased in many of the irradiated lesions. We considered that the decreased number of tumor cells and changes in blood perfusion are some of the factors controlling accumulation in tumors.     

Immunoscintigraphy with indium-111 labeled monoclonal antibodies: the importance of a good display method

A major drawback of In-111-labeled monoclonal antibodies (MoAb) is the presence of intense liver, renal, and bone marrow nonspecific activity. This makes the display of the images hardly optimal and their visual interpretation difficult. In this study, the "intrinsic color scale" (which consists of selecting the limits of the color scale as the highest and the lowest pixel value of the image) was compared to a new, simple algorithm for the determination of the limits of the color scale. This algorithm was based on the count density in the iliac crest areas. OC-125 or anti-CEA In-111 MoAb F(ab')2 fragments were used in 32 patients with suspected recurrence of ovarian (19 patients) or colorectal cancer (13 patients). Final diagnosis was assessed by surgery (21 patients), biopsy (five patients), or followup (six patients). A 10-minute abdomino-pelvic anterior view was recorded two days after injection. These views are displayed using the two methods and interpreted by two observers. Using their responses in each quadrant of the pelvis, the authors calculated two ROC curves. The comparison of the ROC curves showed better performances for the new method. For example, for the same specificity (73%), the sensitivity of the new method was significantly better (78% versus 68%). This result confirmed the importance of a good methodology for displaying immunoscintigraphic images.     

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.     

Significance of diffuse cardiac activity on In-111 labeled leucocyte scans

To assess the significance of diffuse cardiac activity (DCA) seen on In-111 labeled leukocyte scans, we reviewed 87 studies performed over the last 4 years. Inflammatory cardiac conditions were seen as frequently in patients with DCA (15%) as those without (7%, P = 0.3). There was a higher ratio of RBC:WBC in the final WBC preparation in the false-positive DCA group than the true positive DCA and no DCA groups. False-positive studies showing DCA are most likely due to residual blood pool activity.     

In-111 labeled leukocyte imaging in a case of pseudogout.

In-111 labeled leukocyte scintigraphy was performed on a 90-year-old woman who had a fever and left lower extremity pain for 3 days. Leukocyte images demonstrated abnormal activity in the left knee and ankle. Aspiration of the left knee joint yielded cloudy yellow fluid with a leukocyte count of 30,000 per mm3 (75% polymorphonuclear leukocytes, 1% lymphocytes, and 24% monocytes). Cultures of the aspirate were reported as no growth. Microscopic examination of the aspirate revealed the presence of rod-shaped crystals of calcium pyrophosphate dihydrate, confirming the diagnosis of calcium pyrophosphate deposition disease, also known as pseudogout. The acute arthritis of pseudogout stimulates an intense leukocyte response; therefore, labeled leukocyte images performed on patients suspected of having this condition must be interpreted cautiously because scintigraphically it may not be possible to distinguish pseudogout from septic arthritis.     

Significance of diffuse cardiac activity on In-111 labeled leucocyte scans

To assess the significance of diffuse cardiac activity (DCA) seen on In-111 labeled leukocyte scans, we reviewed 87 studies performed over the last 4 years. Inflammatory cardiac conditions were seen as frequently in patients with DCA (15%) as those without (7%, P=0.3). There was a higher ratio of RBC:WBC in the final WBC preparation in the false-positive DCA group than the true positive DCA and no DCA groups. False-positive studies showing DCA are most likely due to residual blood pool activity.Presented in part, 70th annual meeting, Radiological Society of North America, Washington D.C., 25 November 1984     

In-111 labeled leukocyte scintigraphy in a case of multifocal candidiasis

The value of indium-111 labeled leukocyte scintigraphy for the diagnosis of infection in the general population is well documented; there is less information available on its role in the evaluation of the immunocompromised patient. In this study, leukocyte scintigraphy was performed on a 31-year-old immunocompromised woman who had a possible intra-abdominal abscess. No abscess was detected, but intense oral, esophageal, gastric, and vaginal uptake was observed. Candida infection was histologically confirmed at all four sites.     

In-111 labeled monoclonal anti-carcinoembryonic antigen antibody (ZCE025) in the immunoscintigraphic imaging of metastatic antigen-producing adenocarcinomas

The carcinoembryonic antigen (CEA) is a clinically useful marker since it is expressed by adenocarcinomas of diverse origin. Detection and quantitation of circulating CEA levels is used to follow the clinical course of metastatic adenocarcinoma. In this phase I study, the toxicity, pharmacokinetics, and optimal imaging dose of an In-111 labeled monoclonal anti-CEA antibody (ZCE025) was studied in patients with colorectal carcinoma or any CEA-producing tumor. Twenty-four of 26 evaluable patients (92%) demonstrated at least one site of tumor-specific antibody uptake. Sixty-seven sites of metastatic cancer were identified by conventional diagnostic studies. Twenty-nine (43%) of these sites were demonstrable by radioimmune imaging using ZCE025. Twenty-five additional sites of antibody uptake were observed but could not be associated with metastatic deposits. Lymph node and visceral metastases were visualized more frequently than bone, subcutaneous, lung, or liver metastases. Neither tumor size nor antibody dose (2.5-40 mg) appeared to influence the frequency of tumor imaging. The pharmacokinetics of the In-111 labeled antibody fitted a two-compartment model, and patients receiving less than 10 mg of antibody showed a faster clearance of the antibody than those who received greater than 10 mg.     

Subcellular kinetics of In-111 monoclonal antibody in the liver

To evaluate the mechanism for prolonged retention of In-111 monoclonal antibody (MoAb) by the liver, we investigated the subcellular kinetics of the In-111 225.28S, an antimelanoma IgG2a. Forty microCi/10 micrograms of the In-111 MoAb was injected IV into groups of SD rats. The liver was excised at 3, 8, 17, 24, 48 and 72 hr and homogenized with 0.25 M sucrose containing 0.01 M Tris-HCl buffer (pH 7.6). Subcellular fractionation was carried out by 3-step (ultra-)centrifugation. The radioactivity of each fraction including nuclear, mitochondrial (lysosomal), microsomal and supernatant fraction was measured and expressed as a percentage of the total radioactivity of all the fractions. Moreover, the supernatant fraction was assessed by size exclusion HPLC. The supernatant was a predominant fraction of the In-111 radioactivity, 61% at 3 hr, and was decreased with time, 21% at 72 hr (p less than 0.01), while the activity in the mitochondrial fraction continued to increase from 11% to 44%. As compared to these two fractions, the nuclear and microsomal radioactivities were relatively constant, 10-25%, throughout the study. The HPLC analysis revealed that the supernatant In-111 activity at early time points was mainly eluted with an intact IgG and thereafter this major peak activity was reduced with associated activity peaks found in smaller moiety fractions. To compare the In-111 MoAb with the iodine labeled MoAb, we also investigated the subcellular kinetics of the I-125 MoAb in the same manner.(ABSTRACT TRUNCATED AT 250 WORDS)