111In-pentetreotide versus bone scintigraphy in the detection of bony metastases of neuroblastoma.

Bone scintigraphy (BS) is widely utilized for the assessment of bone metastases (BMs) of neuroblastoma (NB). Since 111In-pentetreotide scintigraphy (PS) has been used to image NB with high sensitivity, we compared the sensitivity and specificity of PS with that of BS for the detection of BMs of NB. Nine patients with NB underwent both PS and BS for staging and/or restaging of their disease. The sensitivity and specificity of both imaging approaches were compared based on the findings of histopathology, other conventional imaging methods and subsequent clinical follow-up. In five of the nine patients, both PS and BS were negative for BMs. Radiographic bone surveys (RBSs) were also negative in these patients, except in one who showed a suspicious tibial lesion, but a computed tomography-guided biopsy failed to show evidence of disease. These patients remained without clinical evidence of BMs after a median duration of more than 15 months (range, 6-19 months). In three of four remaining patients, both PS and BS were positive for BMs, whilst only PS was positive in one patient. Overall, PS showed a greater number of BMs (30 vs. 7) with greater conspicuity compared with BS. The initial experience comparing BS with PS suggests that PS may provide a better assessment of the extent of BMs of NB, and that it may be useful as an adjunct to BS at institutions in which 131I- or 123I-metaiodobenzylguanidine is not available, particularly if BS is negative. In patients with similarly positive BS, PS might still provide unique prognostic information beyond that provided by BS. Further studies are therefore warranted.

Role of radiation dosimetry in radioimmunotherapy planning and treatment dosing.

Cancer-seeking antibodies (Abs) carrying radionuclides can be powerful drugs for delivering radiotherapy to cancer. As with all radiotherapy, undesired radiation dose to critical organs is the limiting factor. It has been proposed that optimization of radioimmunotherapy (RIT), that is, maximization of therapeutic efficacy and minimization of normal tissue toxicity, depends on a foreknowledge of the radiation dose distributions to be expected. The necessary data can be acquired by established tracer techniques, in individual patients, using quantitative radionuclide imaging. Object-oriented software systems for estimating internal emitter radiation doses to the tissues of individual patients (patient-specific radiation dosimetry), using computer modules, are available for RIT, as well as for other radionuclide therapies. There is general agreement that radiation dosimetry (radiation absorbed dose distribution, cGy) should be utilized to establish the safety of RIT with a specific radiolabeled Ab in the early stages (i.e. phase I or II) of drug evaluation. However, it is less well established that radiation dose should be used to determine the radionuclide dose (amount of radioactivity, GBq) to be administered to a specific patient (i.e. radiation dose-based therapy). Although treatment planning for individual patients based upon tracer radiation dosimetry is an attractive concept and opportunity, particularly for multimodality RIT with intent to cure, practical considerations may dictate simpler solutions under some circumstances.

Initial experience with high-dose radioimmunotherapy of metastatic medullary thyroid cancer using 131I-MN-14 F(ab)2 anti-carcinoembryonic antigen MAb and AHSCR.

UNLABELLED: This phase I study was initiated to determine the toxicity and therapeutic potential of high-dose 131I-MN-14 F(ab)2 anti-carcinoembryonic antigen monoclonal antibody (MAb) combined with autologous hematopoietic stem cell rescue (AHSCR) in patients with rapidly progressing metastatic medullary thyroid cancer. METHODS: Twelve patients were entered into the study. Dose escalation was based on prescribed radiation doses to critical organs (i.e., kidney, lung, and liver). Starting doses were 900 cGy to the kidney and no more than 1200 cGy to the lung and liver, with dose increments of 300 cGy until the maximum tolerable dose is determined. Tumor targeting was assessed by external scintigraphy, toxicity was assessed according to the common toxicity criteria of the National Cancer Institute, and therapy responses were assessed by CT, serum carcinoembryonic antigen, and calcitonin. RESULTS: One patient received 9.95 GBq 131I-MN-14 F(ab)2, for an initial dose of 656 cGy to critical organs, 8 received 900 cGy (8.69-17.98 GBq), and 3 received 1200 cGy (15.17-17.69 GBq). The MAb scans of all patients showed positive findings. Autologous hematopoietic stem cells were given to all patients 1-2 wk after therapy, when the total body radiation exposure was less than 5.2 x 10(-7) C/kg/h. Dose-limiting toxicity, defined as grade 3 or 4 nonhematologic toxicity, was not seen in the patient who received the 656-cGy dose, and only 1 of the 8 patients treated at the 900-cGy dose level had grade 3 toxicity, which was gastrointestinal and reversible. No dose-limiting toxicity was seen in the 3 patients treated at the 1200-cGy dose level. Except for the instance of grade 3 gastrointestinal toxicity, nonhematologic toxicity was relatively mild, with only grade 1 or 2 toxicity observed in 9 patients. No renal toxicity was seen. Of the 12 patients, 1 had partial remission for 1 y, another had a minor response for 3 mo, and 10 had stabilization of disease lasting between 1 and 16 months. CONCLUSION: The results show the safety of administering high myeloablative doses of 131I-MN-14 F(ab)2 with AHSCR in patients with metastatic medullary thyroid cancer. The antitumor responses in patients with aggressive, rapidly progressing disease are encouraging and warrant further research to optimize the effectiveness of this new treatment.

Progressive intermediate-grade non-Hodgkin's lymphoma after high-dose therapy and autologous peripheral stem-cell transplantation: changing the natural history with monoclonal antibody therapy.

The prognosis of patients with progressive intermediate-grade non-Hodgkin's lymphoma (NHL) after high-dose chemotherapy and autologous peripheral stem-cell transplantation (PSCT) is poor, with survival measured in months. The advent of monoclonal antibody therapy for NHL has created new options for effective therapy with relatively mild side effects. We report on two patients with progressive intermediate-grade NHL after PSCT who were treated with monoclonal antibody therapy. Both patients initially received rituximab (unlabeled anti-CD20 monoclonal antibody) and were subsequently treated with (90)Y-epratuzumab (yttrium-90-labeled humanized anti-CD22 monoclonal antibody) at relapse. One patient received (90)Y-epratuzumab alone while the other was treated with higher doses in combination with autologous peripheral stem-cell infusion. Both patients achieved a rapid response to the radiolabeled antibody with minimal toxicity. Monoclonal antibody therapy may be an effective and tolerable treatment for progressive NHL after PSCT.

Prediction of hematologic toxicity after radioimmunotherapy with (131)I-labeled anticarcinoembryonic antigen monoclonal antibodies.

UNLABELLED: This study was undertaken to determine the factors affecting myelotoxicity after radioimmunotherapy (RAIT) with 131I-labeled anticarcinoembryonic antigen (anti-CEA) monoclonal antibodies (MAbs). METHODS: Ninety-nine patients who received 131I-labeled MN-14 or NP-4 anti-CEA MAbs for the treatment of CEA-producing cancers were assessed for platelet and white blood cell (WBC) toxicity based on the common Radiation Therapy Oncology Group (RTOG) criteria. Univariate and multivariate regression analyses were used to identify the statistically significant factors affecting toxicity among the following variables: red marrow dose, baseline platelet and WBC counts, bone or marrow (or both) metastases, prior chemo- or radiotherapy, timing of prior chemo- or radiotherapy in relation to RAIT, type and number of prior chemotherapeutic regimens, age, sex, antibody form and cancer type. RESULTS: Red marrow dose, baseline platelet or WBC counts and multiple bone or marrow (or both) metastases were the only significant factors affecting hematologic toxicity according to both univariate and multivariate analyses, whereas chemotherapy, 3-6 mo before RAIT, was significant according to multivariate analysis. In this retrospective study, the multivariate regression equations using these four variables provided an exact fit for postRAIT platelet toxicity grade (PltGr) and WBC toxicity grade (WBCGr) in 40% and 46%, respectively, of the 99 patients included in the analysis. Moreover, severe (grade 3 or 4) PltGr and WBCGr could be classified accurately in all cases, whereas nonsevere (grade 0, 1, or 2) PltGr and WBCGr could be classified accurately in all but 6 of 13 cases of grade 2 toxicity, in which a severe toxicity grade was estimated using the regression equations. CONCLUSION: Red marrow dose, baseline blood counts, multiple bone or marrow (or both) metastases and recent chemotherapy are the most important factors related to hematologic toxicity after RAIT. This study provides a simple model for predicting myelotoxicity with reasonable accuracy in most patients. In addition, the identification of bone or marrow (or both) metastases and recent chemotherapy as significant factors for myelotoxicity may be important in the future design of clinical trials.

Pharmacokinetics, dosimetry, and initial therapeutic results with 131I- and (111)In-/90Y-labeled humanized LL2 anti-CD22 monoclonal antibody in patients with relapsed, refractory non-Hodgkin's lymphoma.

The pharmacokinetics, dosimetry, and immunogenicity of 131I- and (111)In-/90Y-humanized LL2 (hLL2) anti-CD22 monoclonal antibodies were determined in patients with recurrent non-Hodgkin's lymphoma. Fourteen patients received tracer doses of 131I-hLL2 followed 1 week later by therapeutic doses intended to deliver 50-100 cGy to the bone marrow. Another eight patients received (111)In-hLL2 followed by therapy with 90Y-hLL2 also delivering 50 or 100 cGy to the bone marrow. The blood T(1/2) (hours) for the tracer infusions of 131I-hLL2 was 44.2 +/- 10.9 (mean +/- SD) compared with 54.2 +/- 25.0 for the therapy infusions, whereas the values were 70.7 +/- 17.6 for (111)In-hLL2 and 65.8 +/- 15.0 for 90Y-hLL2. The estimated average radiation dose from 131I-hLL2 in tumors >3 cm was 2.4 +/- 1.9 cGy/mCi and was only 0.9-, 1.0-, 1.1-, and 1.0-fold that of the bone marrow, lung, liver, and kidney, respectively. In contrast, the estimated average radiation dose from 90Y-hLL2 in tumors >3 cm was 21.5 +/- 10.0 cGy/mCi and was 3.7-, 2.5-, 1.8-, and 2.5-fold that of the bone marrow, lung, liver, and kidney, respectively. No evidence of significant anti-hLL2 antibodies was seen in any of the patients. Myelosuppression was the only dose-limiting toxicity and was greater in patients who had prior high-dose chemotherapy. Objective tumor responses were seen in 2 of 13 and 2 of 7 patients given 131I-hLL2 or 90Y-hLL2, respectively. In conclusion, 90Y-hLL2 results in a more favorable tumor dosimetry compared with 131I-hLL2. This finding, combined with the initial anti-tumor effects observed, encourage further studies of this agent in therapeutic trials.

Importance of timing of radioimmunotherapy after granulocyte colony-stimulating factor administration for peripheral blood stem cell harvest.

Nine radioimmunotherapy (RAIT)-naive patients with medullary thyroid cancer received high doses of 131I-MN-14 F(ab)2 anti-carcinoembryonic antigen monoclonal antibody (232-486 mCi), five in combination with bone marrow harvest, without prior granulocyte colony stimulating factor (G-CSF) injections (group 1) and the other four using peripheral blood stem cell harvest (PBSCH) preceded by G-CSF administration of 10 microg/kg per day for 5 days for stem cell mobilization, 6-8 days before RAIT (group 2). The amounts of radioactivity (mCi) given in both groups were similar (312 +/- 93 versus 424 +/- 65; P = NS). The percent platelet loss at nadir, duration of grade 4 thrombocytopenia, and time to complete recovery (TTCR, measured from the day of treatment), were 83 +/- 17%, 2.5 +/- 0.7 days, and 45 +/- 8 days in group 1, respectively, compared with 88 +/- 6%, 3.0 +/- 2.6 days, and 50 +/- 24 days in group 2 (P = NS), respectively. In contrast, the percent WBC loss at nadir, duration of grade 4 leukopenia, and TTCR of WBCs were 72 +/- 12%, 0.0 +/- 0.0 day, and 42 +/- 12 days in group 1, respectively, compared with 93 +/- 3%, 8.0 +/- 3.6 days, and 263 +/- 136 days in group 2, respectively (P < 0.02, 0.03, and 0.05 for differences of percent loss, duration of nadir, and TTCR, respectively). The difference in WBC toxicity after RAIT with bone marrow harvest and PBSCH is thought to be due to the administration of G-CSF for stem cell mobilization within 1 week before RAIT, which may sensitize the "endogenous" granulocyte precursors to subsequent RAIT. Preclinical data of RAIT in mice showed that the time of G-CSF administration before RAIT is critical: increased WBC toxicity was seen in mice given RAIT 3 or 7 days after a 5-day course of G-CSF (81 and 57% WBC loss, respectively) compared with those given no G-CSF or G-CSF 10 or 14 days before RAIT (45-50%) WBC loss). In conclusion, our data indicate that the timing of RAIT after the administration of G-CSF for PBSCH may influence WBC toxicity and recovery after this treatment and may have important implications on the design of high-dose RAIT trials combined with PBSCH.

Phase I/II trial of (131)I-MN-14F(ab)2 anti-carcinoembryonic antigen monoclonal antibody in the treatment of patients with metastatic medullary thyroid carcinoma.

BACKGROUND: Monoclonal antibodies (MAbs) against carcinoembryonic antigen (CEA) have been recognized as targeting agents for medullary thyroid carcinoma (MTC). This Phase I/II study was initiated to determine the safety, maximum tolerated dose (MTD), and therapeutic potential of (131)I-MN-14 F(ab)2 anti-CEA MAb for patients with metastatic MTC. METHODS: Fifteen patients were enrolled in this study. Dose escalation was based on estimates of radiation dose to the bone marrow, and the radioactive dose given was determined by a pretherapy diagnostic study in which 8 mCi (0.6-20 mg) of (131)I-MN-14 F(ab)2 was administered 1 week prior to therapy. RESULTS: Three patients received an initial dose of 140 centigray (cGy) to bone marrow, 11 received 180 cGy, and 1 received 220 cGy. Myelosuppression was the only significant treatment-related dose-limiting toxicity (DLT), and the MTD appeared to be 180 cGy to the bone marrow. Human antimouse antibodies (HAMA) developed in 8 patients 2-6 weeks after therapy. Seven patients had a median of 55% reduction of tumor markers. One patient showed a dramatic improvement in the mass effect on the airways caused by 3 tumor lesions in the neck, with a 45% reduction of overall tumor burden. The disease has continued to be radiologically stable in 11 of 12 assessable patients for periods ranging from 3+ to 26+ months. CONCLUSIONS: Therapy with (131)I-MN-14 F(ab)2 is well tolerated and shows evidence of biochemical and radiologic antitumor activity. HAMA development suggests that humanized MAbs will be required in trials with repeated dose schedules. Further dose escalation, alone or in combination with other therapy modalities, is indicated for future trials, preferably with humanized anti-CEA MAbs.

Factors influencing hematologic toxicity of radioimmunotherapy with 131I-labeled anti-carcinoembryonic antigen antibodies.

BACKGROUND: Several investigators have reported a considerable variability in the observed hematologic toxicity after radioimmunotherapy (RAIT) with monoclonal antibodies (MoAb) given at similar amounts of radioactivity based on body surface area and/or similar radiation absorbed doses given to the red marrow. The authors investigated various factors potentially affecting hematologic toxicity after RAIT with 131I-labeled anti-carcinoembryonic antigen (CEA) MoAb to identify the statistically significant factors from those commonly perceived clinically to substantially contribute to this toxicity. METHODS: Ninety-nine patients who received 131I-labeled anti-CEA MoAb for the treatment of CEA-producing cancers were assessed for platelet and white blood cell toxicity based on the common Radiation Therapy Oncology Group criteria. Multivariate regression analysis was used to identify the statistically significant factors affecting toxicity among the following variables: red marrow dose, baseline platelet and white blood cell counts, bone and/or marrow metastases, prior chemotherapy or radiotherapy, timing of prior chemotherapy or radiotherapy in relationship to RAIT, type and number of prior chemotherapeutic regimens, age, sex, antibody form, and cancer type. RESULTS AND CONCLUSIONS: Red marrow dose, baseline platelet or white blood cell counts, multiple bone and/or marrow metastases, and chemotherapy 3-6 months before RAIT were the only four significant factors affecting hematologic toxicity according to multivariate analysis. The identification of bone and/or marrow metastases and recent chemotherapy as significant factors for hematologic toxicity could be important in the design of future clinical trials.

Phase I/II clinical radioimmunotherapy with an iodine-131-labeled anti-carcinoembryonic antigen murine monoclonal antibody IgG.

UNLABELLED: The aim of this study was to determine, in a Phase I/II clinical trial, the pharmacokinetics, dosimetry and toxicity, as well as antitumor activity, of the 131I-labeled murine anti-carcinoembryonic antigen (CEA) monoclonal antibody, NP-4 (IgG1 subtype). METHODS: A total of 57 patients with CEA-expressing tumors (29 colorectal, 9 lung, 7 pancreas, 6 breast and 4 medullary thyroid cancer patients), mostly in very advanced stages, were treated. The patients underwent a diagnostic study (1-3 mg of IgG and 8-30 mCi of 131I) to assess tumor targeting and to estimate dosimetry, followed by the therapeutic dose (4-23 mg and 44-268 mCi), based on the radiation dose to the red marrow. Imaging was performed from 4-240 hr postinjection (planar and SPECT). Blood and whole-body clearance were determined; radiation doses were calculated by the Medical Internal Radiation Dose scheme. RESULTS: Red marrow doses ranged from 45 to 706 cGy, and whole-body doses ranged from 31 to 344 cGy. Differences in pharmacokinetics were found between different types of CEA-producing tumors: blood T 1/2 was significantly lower in colorectal cancer when compared to all other tumor types (21.4 +/- 11.1 hr versus 35.8 +/- 13.2 hr, p < 0.01), as was also whole-body t 1/2. Myelotoxicity was dose-limiting, and its severity was related to the types of prior therapy and extent of bone marrow involvement. In patients without prior radiation or chemotherapy, marrow doses as high as 600 cGy were tolerated without evidence of dose-limiting toxicity. No major toxicity to other organs was observed. Tumor doses were inversely related to the tumor mass and ranged between 2 and 218 cGy/mCi. Modest antitumor effects were seen in 12 of 35 assessable patients (1 partial remission, 4 minor/mixed responses and 7 with stabilization of previously rapidly progressing disease). CONCLUSION: These results suggest that prior chemotherapy or external beam radiation is an important risk factor for the development of hematological toxicity in radioimmunotherapy and that higher radiation doses may be delivered to tumors of patients without prior therapy compromising the bone marrow reserve. The different and, in the individual cases, unpredictable clearance rates suggest the necessity of dosimetry-based treatment planning rather than mCi/m2 dosing. Small tumors seem to be more suitable for radioimmunotherapy because of their favorable dosimetry, but to achieve better therapeutic results in patients with bulky disease, the application of higher, potentially myeloablative doses is indicated.

Advantage of residualizing radiolabels for an internalizing antibody against the B-cell lymphoma antigen, CD22.

LL2 is an anti-CD22 pan-B-cell monoclonal antibody which, when radiolabeled, has a high sensitivity for detecting B-cell, non-Hodgkin's lymphoma (NHL), as well as an antitumor efficacy in therapeutic applications. The aim of this study was to determine whether intracellularly retained radiolabels have an advantage in the diagnosis and therapy of lymphoma with LL2. In vitro studies showed that iodinated LL2 is intracellularly catabolized, with a rapid release of the radioiodine from the cell. In contrast, residualizing radiolabels, such as radioactive metals, are retained intracellularly for substantially longer. In vivo studies were performed using LL2-labeled with radioiodine by a non-residualizing (chloramine-T) or a residualizing method (dilactitol-tyramine, DLT), or with a radioactive metal (111In). The biodistribution of a mixture of 125I (non-residualizing chloramine-T compared to residualizing DLT), 111In-labeled LL2 murine IgG2a or its fragments [F(ab')2, Fab'], as well as its humanized, CDR-grafted form, was studied in nude mice bearing the RL human B-cell NHL cell line. Radiation doses were calculated from the biodistribution data according to the Medical International Radiation Dose scheme to assess the potential advantage for therapeutic applications. At all assay times, tumor uptake was higher with the residualizing labels (i.e., 111In and DLT-125I) than with the non-residualizing iodine label. For example, tumor/blood ratios of 111In-labeled IgG were 3.2-, 3.5- and 2.8-fold higher than for non-residualizing iodinated IgG on days 3, 7 and 14, respectively. Similar results were obtained for DLT-labeled IgG and fragments with residualized radiolabels. Tumor/organ ratios also were higher with residualizing labels. No significant differences in tumor, blood and organ uptake were observed between murine and humanized LL2. The conventionally iodinated anti-CD20 antibody, 1F5, had tumor uptake values comparable to those of iodinated LL2, the uptake of both antibodies being strongly dependent on tumor size. These data suggest that, with internalizing antibodies such as LL2, labeling with intracellularly retained isotopes has an advantage over released ones, which justifies further clinical trials with residualizing 111In-labeled LL2 for diagnosis, and residualizing 131I and 90Y labels for therapy.

Variables influencing tumor dosimetry in radioimmunotherapy of CEA-expressing cancers with anti-CEA and antimucin monoclonal antibodies.

UNLABELLED: In this study, we examined the factors that may influence tumor dosimetry in the radioimmunotherapy of solid, CEA-expressing cancers. METHODS: Data from 119 tumors in 93 patients with CEA-expressing cancers were analyzed. The patients underwent radioimmunotherapy with the 131I-labeled IgG1 anti-CEA antibodies NP-4 (Ka = 10(8) M-1) or MN-14 (Ka = 10(9) M-1), its humanized form hMN-14, as well as the anticolon-specific antigen-p (CSAp) antibody, Mu-9. For dosimetry, the biodistribution, targeting kinetics and cumulated activity of tumors and organs were determined from planar and SPECT imaging. RESULTS: An inverse logarithmic relationship between tumor size and antibody uptake was found for both anti-CEA antibodies, whereas no such relationship was found for Mu-9. The absolute tumor uptake was identified as the most important factor determining the radiation dose to the tumor (r = 0.9), with the biological half-life of the antibody in the tumor being of secondary importance (r = 0.5). No significant difference in tumor uptake was found between both anti-CEA antibodies, despite their tenfold difference in affinity. At comparable masses, colorectal and medullary thyroid cancers had significantly higher tumor uptakes (p = 0.02), as well as tumor-to-red marrow dose ratios, than other cancer types. The tumor half-lives of the anti-CEA antibodies were significantly lower in colorectal than in all other tumor types (p = 0.01). CONCLUSION: In radioimmunotherapy, tumor uptake appears to be the most important dose-determining factor. Differences in antibody affinity are reflected by differences in the biological half-life, not the absolute uptake. Especially favorable conditions for anti-CEA antibodies seem to prevail in colorectal cancer patients having minimal disease, as well as in medullary thyroid cancer, where cytotoxic tumor doses might be expected. Antimucin antibodies may have a particular advantage in the treatment of patients with larger colorectal tumors.

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.

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.

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.

Reduction of the renal uptake of radiolabeled monoclonal antibody fragments by cationic amino acids and their derivatives.

The renal uptake of radiolabeled antibody fragments and peptides is a problem in radioimmunodetection and radioimmunotherapy, especially with intracellular retained radiometals. The aim of this study was to develop suitable methods to reduce this kidney uptake. BALB/c mice or nude mice bearing the human GW-39 colon carcinoma xenograft were given i.p. injections of basic amino acids or a range of different basic amino acid derivatives, amino sugars, as well as cationic peptides. The effect of these agents on the biodistribution of Fab' and F(ab')2 fragments of different mAbs radiolabeled with 99mTc, 188Re, 111In, 88Y, or 125I was studied. Tumor and organ uptake was determined and compared to untreated mice. The kidney uptake of Fab' fragments was reduced 5-6-fold in a dose-dependent manner as compared to untreated controls. The uptake in all other organs, as well as the tumor, was unaffected. A similar reduction in renal retention was seen for all other intracellularly retained isotopes, as well as for F(ab')2 fragments. D- and L-isomers of lysine were equally effective whether given i.p. or p.o. D-glucosamine was effective, but its N-acetyl derivative was not. Basic polypeptides (e.g., poly-L-lysine) were also effective; their potency increased with increasing molecular weight. HPLC of the urine taken from treated animals showed the excretion of intact Fab', in contrast to mostly low-molecular-weight metabolites in the control group. These studies indicate that a variety of basic compounds is capable of inhibiting the tubular reabsorption of peptides and proteins, thus lowering the kidney uptake of antibody fragments significantly. On a molecular basis, the effect seems to essentially rely on the presence of a positively charged amino group. By reducing renal retention of antibody fragments, their role as imaging and therapeutic agents may be expanded.