Palliative radiation with a radiolabeled diphosphonate (rhenium-186 etidronate) in patients with hormone-refractory disseminated prostate carcinoma.

MATERIAL AND METHODS: The present study investigates the safety and efficacy of 2590 MBq rhenium-186 (186Re) etidronate (i.e. twice the activity normally used) administered intravenously in 15 patients with disseminated prostatic carcinoma and bone pain. RESULTS: Pain relief was observed in 11 of 14 evaluable patients (79%), 4 of whom became completely free from pain. Five of the responding patients also noted an improvement in daily activity and two found it possible to reduce or discontinue morphine medication. Pain relief occurred within one week in four patients, and within two weeks in eight of the responding patients. The mean duration of pain relief after the first course of 186Re-etidronate was 6 weeks (range 4-10). The toxicity was mild (< or = grade 2), transient, and restricted to hematological toxicity. CONCLUSIONS: 186Re-etidronate provided rapid pain-relief and had mild toxicity in most patients with disseminated hormone-refractory prostatic carcinoma, but doubling the activity did not markedly improve the efficacy.

Comparison of 125I- and (111)In-labeled monoclonal antibody BR96 for tumor targeting in combination with extracorporeal immunoadsorption.

Extracorporeal whole blood immunoadsorption (ECIA) accelerates the clearance of radiolabeled monoclonal antibodies (mAbs) without significantly affecting tumor uptake by removing the excess of these mAbs from the blood, thus increasing tumor:normal tissue (T:N) ratios. The present study is focused on comparing the capacity of ECIA in tumor targeting with the same mAb (chiBR96-biotin) labeled with either (111)In or 125I. Forty-five Brown Norwegian rats with syngeneic rat colon carcinoma isografted both in liver and intramuscularly were used. chiBR96 is a highly tumor-specific mAb directed against the Lewis-type antigen. ECIA of whole blood was started 15 h after the injection of 125I- or (111)In-labeled BR96-biotin. The procedure lasted for 2 h and was repeated for (111)In-labeled BR96-biotin in a few rats after 3 or 24 h. ECIA reduced the whole body activity by the same magnitude (between 39% and 52%), irrespective of whether (111)In- or 125I-labeled chiBR96 was used. A similar observation was also made for the reduction in blood radioactivity after ECIA (79-94%). Time-activity curves during ECIA showed that the major reduction (approximately 85%) in blood radioactivity occurred during the first 45-60 min. Repeating the ECIA with (111)In-BR96 caused only an additional minimal reduction of blood activity, whereas a further reduction of whole body activity of 14-20% was achieved. The T:N uptake ratios were significantly enhanced immediately after ECIA with (111)In- or 125I-labeled chiBR96. Due to greater accumulation of (111)In-BR96 in tumors, a long-term improvement in T:N ratios was obtained after ECIA compared with 125I-labeled BR96. Our results therefore indicate that (111)In/(90Y)-labeled BR96-biotin could be more advantageous than 125I/131I for radioimmunotargeting/radioimmunotherapy in combination with ECIA due to better activity retention by the tumor.

Radioimmunotherapy using 131I-labeled anti-CD22 monoclonal antibody (LL2) in patients with previously treated B-cell lymphomas.

Experience in using rapidly internalizing antibodies, such as the anti-CD22 antibody, for radioimmunotherapy of B-cell lymphomas is still limited. The present study was conducted to assess the efficacy and toxicity of a 131I-labeled anti-CD22 monoclonal antibody (mAb), LL2, in patients with B-cell lymphomas failing first- or second-line chemotherapy. Eligible patients were required to have measurable disease, less than 25% B cells in unseparated bone marrow, and an uptake of 99mTc-labeled LL2Fab' in at least one lymphoma lesion on immunoscintigram. Eight of nine patients examined with immunoscintigraphy were unequivocally found to have an uptake, and therapy with 131I-labeled anti-CD22 [1330 MBq/m2 (36 mCi/m2)] preceded by 20 mg of naked anti-CD22 mAb was administered. Three patients achieved partial remission (duration, 12, 3, and 2 months), and one patient with progressive lymphoma showed stable disease for 17 months. Four patients exhibited progressive disease. The toxicity was hematological. Patients with subnormal counts of neutrophils or platelets before therapy seemed to be more at risk for hematological side effects. Radioimmunotherapy in patients with B-cell lymphomas using 131I-labeled mouse anti-CD22 can induce objective remission in patients with aggressive as well as indolent lymphomas who have failed prior chemotherapy.

Improving tumor-to-normal-tissue ratios of antibodies by extracorporeal immunoadsorption based on the avidin-biotin concept: development of a new treatment strategy applied to monoclonal antibodies murine L6 and chimeric BR96.

BACKGROUND: Several strategies have been explored to accelerate monoclonal antibody (MAb) conjugate clearance without affecting intratumoral uptake. One of the most promising is extracorporeal immunoadsorption (ECIA), in which excess radiolabeled MAb circulating in blood is removed. METHODS: Extracorporeal immunoadsorption (ECIA) based on the avidin-biotin concept enables direct adsorption of radiolabeled and biotinylated MAb from plasma and consequently increases the tumor-to-normal-tissue uptake ratio by reducing background radioactivity in all radiosensitive organs. Because the concept is based on an antibody's being biotinylated prior to injection, the blood clearance efficiency is independent of the idiotype or isotype of the antibody employed. As a result, there is no need to develop new adsorption columns for each antibody system used. We have technically simplified the method recently by removing biotinylated MAb directly from blood without separation from plasma preceding the removal. The current study focused on both the development of ECIA and evaluating the effects of ECIA in terms of tumor targeting with two biotinylated radiolabeled MAbs that have different biokinetics, namely, murine MAb L6 and chimeric Mab BR96. RESULTS: The start time of ECIA should be determined for each MAb individually before radioimmunotherapy and be based on previous tumor biokinetics. BR96 with rapid tumor targeting seems more suitable than L6 for the ECIA procedure; it allows the procedure to start earlier and thereby further reduce whole body activity and exposure of critical organs to radiation. CONCLUSIONS: ECIA enables direct adsorption of radiolabeled and biotinylated monoclonal antibody from blood and consequently increases the tumor-to-normal-tissue uptake ratio. The method is even applicable to both the internalizing and already highly tumor-selective BR96 in a syngeneic tumor model.

Extracorporeal whole-blood immunoadsorption enhances radioimmunotargeting of iodine-125-labeled BR96-biotin monoclonal antibody.

UNLABELLED: This study investigates the efficacy of tumor radioimmunotargeting with 125I-labeled BR96-biotin monoclonal antibody using a new method, whole-blood immunoadsorption (WBIA), based on direct adsorption of unbound monoclonal antibody (MAb) from blood without preceding separation of plasma. METHODS: Highly tumor-reactive, internalizing, chimeric BR96 MAb of isotype IgG1 binds to a tumor-associated Lewis-type (Le(Y)) cell surface antigen. Forty-six Brown Norwegian male rats were inoculated intramuscularly and beneath the liver or kidney capsule with syngeneic rat colon carcinoma BN7005, expressing Lewis-type antigen, and investigated. The rats were injected intravenously with 3.5-4.5 MBq 125I-labeled BR96-biotin. Twenty of the rats underwent WBIA starting 5 or 12 hr after injection. About six blood volumes were passed through an avidin-gel adsorption column during 2 hr. RESULTS: By using WBIA, whole-body radioactivity was reduced by 50%, and plasma activity by 85%. Both directly after completion of WBIA and 33 hr later, the activity uptake in tumors manifested only a nonsignificant decrease as compared with corresponding controls (p > 0.05) and had approximately similar time-activity curves. Uptake ratios for tumor (T):bone marrow, T:liver, T:kidney and T:lung were enhanced 2.3- to 3.5-fold in all three tumor models, as compared with controls. The ratio of liver tumor to bone marrow was improved from 10:1 to 30:1. CONCLUSION: This new method of WBIA yields significantly improved radioimmunotargeting of highly tumor-reactive, internalizing MAb BR96.

Extracorporeal immunoadsorption from whole blood based on the avidin-biotin concept. Evaluation of a new method.

This study of 36 rats with rat colon adenocarcinoma transplants was carried out to investigate the efficacy of a new method of whole blood immunoadsorption (WBIA) in removing biotinylated monoclonal antibodies (MAbs) directly from unseparated blood, in order to increase 'the tumor/normal-tissue uptake ratio', as compared with extracorporeal immunoadsorption (ECIA) of antibodies from plasma. Compared with the ECIA system, the overall volume of the WBIA system (comprising only a pump, an adsorption column, a drop-chamber and tubings) was less (3.6 vs. 6.2 ml), and procedure duration 2 h less. The 17 rats undergoing the WBIA procedure, started 12 h after i.v. injection of 4.0-4.5 MBq 125I-BR96-biotin, manifested neither hemolysis nor any other complication; no signs of organ edema were found at dissection; whole body and blood radioactivity values were reduced by 51% and 89.5%, respectively. The WBIA method was as effective as ECIA, but technically simpler, safer and more reliable.

Enhanced radioimmunotargeting of 125I-labeled L6-biotin monoclonal antibody (MAb) by combining preload of cold L6 MAb and subsequent immunoadsorption in rats.

The present study investigates whether tumor:normal tissue uptake ratios of radiolabeled monoclonal antibodies can be further improved by a combination of extracorporeal immunoadsorption (ECIA) and preload with unlabeled idiotypic monoclonal antibody. Athymic rats, heterotransplanted with human lung carcinoma under the kidney capsule (SR tumor) and i.m. (IM tumor), were divided into four study groups: controls, ECIA, preload, and combined preload+ECIA. The preload+ECIA procedure reduced the whole-body and plasma activity by 48 and 89%, respectively. After such combined procedure, the uptake of 125I-labeled L6-biotin in SR tumors was unchanged, while the uptake in normal tissues was considerably reduced. Tumor (T):bone marrow ratio was then increased by 17.5 times (after ECIA) and by 4.5 times (24 h after ECIA). Similar enhancements were achieved for T:liver and T:kidney ratios. For the IM tumors, the ratios were not as high as for SR tumors. The effects on T:normal ratios of preload+ECIA in combination were synergistic. The combined procedure resulted both in an increased uptake and prolonged persistence of 125I-labeled L6-biotin in the SR tumors and also in a reduction of corresponding uptake values in organs critical for radiation.

Improving radioimmunotargeting of tumors: the impact of preloading unlabeled L6 monoclonal antibody on the biodistribution of 125I-L6 in rats.

In the radioimmunotherapy of malignancies the uptake of monoclonal antibodies (MoAb) is commonly low in tumors compared with normal tissue. Several methods have been suggested to increase the tumor-to-normal tissue (T/N) ratio. In this study we have investigated the biodistribution of different amounts of 125I-L6-biotin MoAb in combination with a preload of unlabeled L6 MoAb. Nude rats were injected with 50 micrograms or 250 micrograms of unlabeled L6 24 hours prior to the injection of 10 micrograms, 50 micrograms or 250 micrograms of 125I-L6, antipancarcinoma MoAb. Dissections were performed 24 hours after the injection of radiolabeled MoAb. The maximal enhancement of tumor uptake with simultaneously decreased uptake in normal tissues was with 250 micrograms of 125I-L6 preceded by a preload of 50 micrograms unlabeled L6. Mean T/N ratios were improved by a factor of 2.9 for bone marrow, 3.4 for liver, 3.7 for lungs and 2.3 for kidneys as compared with the corresponding controls. This study demonstrated that preinjection of optimal amounts of unlabeled L6 MoAb may increase the uptake of 125I-L6 by tumor and improve the T/N ratios. Based on present data, preloading with unlabeled MoAb should be considered in future clinical studies with immunoconjugates to improve the radioimmunotargeting of tumors. It is essential to titrate an appropriate amount of the preload, thus avoiding possible tumor antigen saturation of unlabeled MoAbs but simultaneously decreasing the uptake of subsequently injected radiolabeled MoAb in normal tissues.

Radio-immunotherapy dosimetry with special emphasis on SPECT quantification and extracorporeal immuno-adsorption.

Results from therapeutic trials with radiolabelled monoclonal antibodies are difficult to compare, because of lack of accurate macroscopic and microscopic dosimetry for both tumours and normal tissues. Requirements for such a dosimetry are covered in the paper. Accurate in vivo dosimetric measurement techniques for verification of calculated absorbed doses are also needed to verify treatment planning. In the review, important topics related to dosimetry in therapeutic trials in RIT are covered, such as, absorbed-dose calculations and activity-quantification techniques for planar imaging and SPECT. The latter is particularly discussed, including a summary of different correction techniques. Absorbed-dose calculations and treatment-planning techniques are also discussed. Possible ways of enhancing the therapeutic ratio are reviewed, especially the novel technique with extracorporeal immuno-adsorption. The review could form the basis of the development of future treatment-planning protocols and for dosimetry calculations in radio-immunotherapy, considering some of the most important parameters for approaching an accurate in vivo dosimetry.

A general extracorporeal immunoadsorption method to increase tumor-to-tissue ratio.

The idea of applying extracorporeal immunoadsorption (ECIA) in radioimmunodiagnosis and radioimmunotherapy has been proposed previously. The authors here report on the development of new concept using a general method for ECIA based on biotinylated MoAb adsorbed on an avidin column. Athymic rats heterotransplanted with either human melanomas or human lung carcinoma were injected with iodine-125-labeled biotinylated 96.5 or L6 MoAb, respectively. At 24 or 48 hours after the injection, ECIA was performed by pumping blood through a hollow-fiber plasma filter. The separated plasma then was passed through an absorbent (avidin-agarose) column. The whole ECIA procedure lasted for 3 hours. By this ECIA method, the tumor-to-normal tissue ratios were increased in various tissues (i.e., radiosensitive and blood rich organs) by a factor of four to five.

Improving radioimmonotargeting of tumors. Variation in the amount of L6 MAb administered, combined with an immunoadsorption system (ECIA).

Extracorporeal immunoadsorption (ECIA) is a new method for the selective removal of circulating radiolabeled monoclonal antibodies (MAb) from plasma to increase the uptake in tumor versus normal tissues (T/N-ratio). To ascertain whether the amount of MAb affects T/N ratios immediately and 24 h after ECIA, we used a rat model with two tumor sites--one intramuscular (im) and one below the subrenal capsule (SR). Extracorporeal immunoadsorption was done with an avidin-agarose column after injection of 125I-labeled biotinylated L6 MAb. The animals received 10, 50 or 250 micrograms of L6 only (controls), or followed by ECIA. The efficacy of the procedure in removing plasma activity was 80-95%. For both tumor sites, the highest T/N-ratios were obtained with 10 micrograms L6. All T/N-ratios significantly improved for SR tumors by a factor ranging from 3.2 (lung) to 12.6 (bone marrow). The T/N-ratios were still elevated 24 h after ECIA. Injection of larger amounts of MAb, probably causing a higher degree of tumor saturation, will not necessarily improve the T/N ratio after ECIA.