Immunoscintigraphy of colorectal cancer with 111In labeled anti-CEA monoclonal antibody (ZCE-025)]

Clinical trials with 111In labeled anti-CEA monoclonal antibody (ZCE-025) was initiated. Five patients with colorectal cancer suspected were given an intravenous injection of 1 mg of 111In labeled ZCE-025. Planar and SPECT images were obtained 24 and 72 hours after injection. Surgical operation was performed on all patients between 7 and 10 days post injection. Of 4 primary sites, all were clearly visualized. Intrahepatic metastasis was visualized as higher activity than normal liver in one of two patients. In one patient whose imaging was negative, no residual cancer was found at surgery. Persistent accumulation of 111In in the lymph nodes was also observed in one patient. Surgical exploration of these lymph nodes showed no gross or microscopic evidence of metastases of colon cancer. No side effects were encountered, although HAMA were detected in all 5 patients by 4 weeks after the administration of ZCE-025. Immunoscintigraphy appears useful in distinguishing recurrent tumor from postoperative granuloma. Further investigation directed to the causes of 111In accumulation in tumor-free lymph nodes is required.     

Colorectal carcinoma: detection with indium-111 anticarcinoembryonic- antigen monoclonal antibody ZCE-025

A phase I and II clinical trial with indium-111-labeled anticarcinoembryonic-antigen monoclonal antibody ZCE-025 (In-111 ZCE-025) was initiated. Fifteen patients with colorectal tumors underwent external scintigraphy following the administration of 5.5 mCi (203.5 MBq) In-111 ZCE-025 at doses of 2.5-80.0 mg. Eighteen of 20 documented tumor sites, excluding those in the liver, were detected with In-111 ZCE-025. Lesions less than 1.5 cm could not be detected. Twenty-five percent of liver metastases exhibited positive accumulation of In-111 ZCE-025 at doses of 40-80 mg. No side effects were encountered. Because of the high detection rate of lymph node metastases from colorectal carcinoma with In-111 ZCE-025, this technique may be helpful in preoperative staging of patients with colorectal tumors, as well as in distinguishing recurrent tumors from postoperative or postradiation changes seen on computed tomography scans or other radiologic images.     

Colorectal tumors: scintigraphy with In-111 anti-CEA monoclonal antibody and correlation with surgical, histopathologic, and immunohistochemical findings

A prospective clinical study of 17 patients with a histologic diagnosis of colorectal carcinoma proved at colonoscopy and surgery was performed with indium-111 anticarcinoembryonic-antigen (CEA) monoclonal antibody (MoAb), ZCE-025. MoAb scanning depicted nine of 16 primary colorectal carcinomas on planar scintigrams (true-positive findings = 56%) and ten of 16 lesions on single-photon emission computed tomography (SPECT) scans (true-positive findings = 62%). Liver metastases were detected in three of three patients, and lymph node metastases were detected in one of four patients. Immunohistochemical examination for CEA in resected colorectal cancer tissues demonstrated a positive correlation between MoAb imaging of primary lesions and cytoplasmic-stromal intracellular CEA distribution. There was no correlation between CEA serum levels and lesion detectability with MoAb scanning.     

Alterations in an indium-111 Fab' under conditions of utilization.

This study was conducted to investigate alterations that occur in an indium/111 Fab' of a monoclonal antibody following its in vivo administration. Patients were infused with 111In-Fab' of the monoclonal antibody ZCE-025. Serum and urine specimens were collected from these patients. Starting materials, serum, urine and controls samples were studied by electrophoresis. Animal distribution studies were performed in normal Balb/c mice and, in some cases, nude mice bearing a carcinoembryonic antigen (CEA)/producing human colon tumour since the antibody targets CEA. The studies indicated that the molecule circulated almost totally intact for at least 4 h and to a considerable extent for 24 h, with some evidence for in vivo fragmentation by 24 h. Evidence was also obtained suggesting the formation of a high molecular weight species in some patients. Shortly after infusion, some of the 111In in the urine appeared as the intact Fab', but within hours the majority migrated electro-phoretically as low molecular weight species. We conclude that while the majority of the 111In-Fab' of this particular antibody remains intact and immunoreactive following its administration, the molecule is structurally changed to some degree shortly after its infusion into humans. Since each monoclonal antibody is unique, the degree and rapidity of degradation of its Fab' in vivo could vary markedly from the above and possibly adversely effect its utility as a radiopharmaceutical.     

Radioimmunodetection of occult carcinoembryonic antigen-producing cancer.

This study evaluates the ability of 111In-labeled anti-carcinoembryonic antigen (CEA) monoclonal antibody (Mab) ZCE-025 to detect sites of occult cancer in patients with elevated serum CEA who have negative or equivocal CT scans. One hundred forty patients suspected of having occult cancer were evaluated. Except for elevated CEA levels, all had negative work-ups, including negative or inconclusive CT scans. Eighty-two patients (59%) had positive scans and 58 (41%) had negative scans. Seventy-five of the 82 patients with positive scans had confirmation of at least one Mab-positive lesion (91% positive predictive value). Thirty-eight of the 58 patients with negative scans had negative follow-up (66% negative predictive value). The Mab scan correctly identified at least one site of tumor in 75 of the 95 patients with recurrent or metastatic disease (79% sensitivity) and correctly predicted the absence of disease in 38 of 45 patients (84% specificity).     

Clinical experience with intra lymphatic administration of111In-labelled monoclonal antibody PAY 276 for the detection of pelvic nodal metastases in prostatic carcinoma

The ability of¹¹¹In-PAY 276 (anti prostatic acid phosphatase antibody) in detecting pelvic lymph node metastasis following bipedal intra lymphatic administration was studied in five patients with carcinoma of the prostate. The labeled antibody was injected directly into the lymphatics of each foot. Planar and tomographic images radioactivity content of lymph nodes resected during staging pelvic lymphadenectomy were compared to the histologic and immunoperoxidase findings. Radioactivity in pelvic lymph nodes was prominently seen within 20 min of injection and was present 16 days later. Persistent accumulation of tracer in the lymphatics of the lower extremities was also observed in all patients 16 days post injection. Radioactivity counts in tumor-free lymph nodes were higher than in tumored lymph nodes resected. Our results demonstrate that intra lymphatic administration of¹¹¹In-labeled PAY 276 monoclonal antibody has major technical limitations, and that further research directed at the causes of tracer accumulation in the lymphatics and tumor-free lymph nodes is required.     

Clinical experience with intra lymphatic administration of 111In-labelled monoclonal antibody PAY 276 for the detection of pelvic nodal metastases in prostatic carcinoma

The ability of 111In-PAY 276 (anti prostatic acid phosphatase antibody) in detecting pelvic lymph node metastasis following bipedal intra lymphatic administration was studied in five patients with carcinoma of the prostate. The labeled antibody was injected directly into the lymphatics of each foot. Planar and tomographic images radioactivity content of lymph nodes resected during staging pelvic lymphadenectomy were compared to the histologic and immunoperoxidase findings. Radioactivity in pelvic lymph nodes was prominently seen within 20 min of injection and was present 16 days later. Persistent accumulation of tracer in the lymphatics of the lower extremities was also observed in all patients 16 days post injection. Radioactivity counts in tumor-free lymph nodes were higher than in tumored lymph nodes resected. Our results demonstrate that intra lymphatic administration of 111In-labeled PAY 276 monoclonal antibody has major technical limitations, and that further research directed at the causes of tracer accumulation in the lymphatics and tumor-free lymph nodes is required.     

Axillary lymphoscintigraphy by radioimmunodetection of carcinoembryonic antigen in breast cancer

In seven women with carcinoma of the breast I-131-labeled antibodies to carcinoembryonic antigen (CEA) were administered subcutaneously in the finger webs. Subsequent scintigraphic immages demonstrated localization of radioactivity in the ipsilateral axillary metastases of all patients and in the contralateral axillae of three. Fifteen patients with either gastrointestinal or genitourinary cancers were studied as controls; in 12 both the hands and feet were injected with antibodies to CEA and in the other three either the hands or feet. Radioactivity was observed in the inquinal nodes of four control patients with tumors below the diaphragm and in the axillary nodes of one patient with a tumor above the diaphragm. The concentration of antibody in lymph node metastases from breast carcinoma was 100% specific. In those lymph nodes that presumably contained no metastatic tumor but demonstrated localization of labeled antibody, retention of CEA in the nodes from tumor drainage is postulated as the receptor site for the antibody.     

Localization of indium-111 in human malignant tumor xenografts and control by chelators

The kinetics of soluble indium-111 ((111)In) in human malignant tumor xenografts and cells was investigated in combination with chelators. Firstly, without chelator, the kinetics of (111)In-chloride was investigated in vitro and in vivo using four human malignant neuroblastoma SK-N-MC, pulmonary papillary adenocarcinoma NCI-H441, pulmonary squamous cell carcinoma PC 9, and colon adenocarcinoma LS 180 cells and xenografts. (111)In was incorporated into tumor cells in vitro to a maximum level during a 60-min incubation. A maximum level of radioactivity was demonstrated in vivo in four human malignant tumors xenografted into nude mice at 24 h postinjection of (111)In-chloride. Secondly, the effect of edetate calcium disodium (CaNa2EDTA) on radioactivity in (111)In-labeled tumors xenografts and cells was studied in vitro and in vivo. CaNa2EDTA significantly reduced (111)In-activity from the labeled tumor xenografts, whereas it had no affect on the radioactivity in the labeled cells. Thirdly, the effect of CaNa2EDTA on radioactivity in human malignant tumors xenografted into nude mice injected with (111)In-chloride was investigated. In one group of mice CaNa2EDTA administered intraperitoneally at 1, 22, 34, 46, 58, and 70 h after injection of (111)In-chloride (postadministration), the localization of (111)In at the tumors was significantly decreased at 72 h compared with the control in all four tumor types. In the other group of mice, CaNa2EDTA administered intraperitoneally at 12 and 1 h before injection of (111)In-chloride and 1, 22, 34, 46, 58, and 70 h postinjection (pre- and postadministration), the radioactivity of tumors was also significantly decreased at 72 h, and the reduction was greater than that with use of postadministration. In a comparative study, CaNa3DTPA had a more powerful effect than CaNa2EDTA. In conclusion, (111)In-activity in tumors consists of intracellular and extracellular components, and the extracellular (111)In may be cleared by chelators. Pre- and postadministration of CaNa3DTPA could remove (111)In-nonspecific localization in tumors when (111)In is released from the radiolabeled agents.     

Immunoreactivity and biodistribution of indium-111-labeled monoclonal antibody to a human high molecular weight-melanoma associated antigen

The anti-human, high molecular weight-melanoma associated antigen (HMW-MAA) MoAb 225.28S was chelated with 111In and then tested for its in vitro reactivity with cultured human melanoma cells and for its biodistribution in human melanoma bearing nude mice. In vitro studies showed that the radiolabeled antibody reacted specifically with cultured melanoma cells. However, binding of DTPA to the monoclonal antibody reduced its titer with cultured melanoma cells from 1:1024 to 1:512. Further labeling of the DTPA-antibody conjugate with 111In caused an additional reduction of its titer to 1:128. Injection of the radiolabeled monoclonal antibody into nude mice resulted in the accumulation of significantly (p less than 0.001) higher radioactivity in melanoma tissue than in nude mice injected with either [111In] chloride or 111In-labeled antibody to human acid phosphatase. The specificity of the distribution of the radiolabeled antibody in nude mice also was indicated by its poor localization in lesions other than melanoma (e.g., human prostate carcinoma and chronic abscess). The localization of antibody in liver and kidney was also high, although lower than that achieved in tumor. These results indicate that 111In-labeled monoclonal antibodies to human tumor associated antigens may be useful for localizing malignant lesions. However, there is a need to improve labeling and/or purification of antibody in order to decrease renal and hepatic activity.     

CaNa2EDTA for improvement of radioimmunodetection and radioimmunotherapy with 111In and 90Y-DTPA-anti-CEA MAbs in nude mice bearing human colorectal cancer.

111In and 90Y, dissociated from 111In-labeled-monoclonal antibody (MAb) and 90Y-labeled MAb, may cause deterioration of the image quality in radioimmunodetection (RID) and undesirable irradiation of nontargeted tissue in radioimmunotherapy (RIT), respectively. The aim of this study was to investigate any improvement in RID and RIT with 111In-MAb and 90Y-MAb by pre- and postadministration of calcium disodium ethylenetriaminetetraacetic acid (CaNa2EDTA). METHODS: Murine MAb F33-104 against carcinoembryonic antigen (CEA) was labeled with 111In or 90Y by the diethylenetriamine pentaacetic (DTPA)-anhydride method. The influence of CaNa2EDTA on loss of radioactivity from 111In-MAb or 90Y-MAb in serum was investigated in vitro. The effects of CaNa2EDTA, administered before and after 111In-MAb or 90Y-MAb, on the biodistribution of radioactive isotopes in nude mice bearing human colon adenocarcinoma LS 180 tumor expressing CEA, or human pulmonary carcinoma PC 9 tumor expressing no CEA, were then examined. As a control, 0.9% NaCl was used in both the in vitro and in vivo studies. RESULTS: CaNa2EDTA did not cause any decrease in levels of radioactivity of radiolabeled MAbs. Pre- and post-treatment with CaNa2EDTA reduced radioctivity in both specific and nonspecific tumors at 72 h after 111In-MAb injection resulting in an increase of the specific tumor-to-nonspecific tumor radioactivity ratio. The levels of hepatic and renal radioactivity were also subsequently decreased by CaNa2EDTA. On the other hand, CaNa2EDTA pre- and post-treatment reduced levels of bony, hepatic, and renal radioactivity at 24, 72, and 72 h, respectively, after 90Y-MAb injection, although it had no effect on tumor radioactivity. CONCLUSION: Pre- and post-treatment with CaNa2EDTA would be of great use in humans who undergo RID or RIT with 111In-MAb and 90Y-MAb accompanied by disassociation of the labeled radionuclides.     

Effect of DTPA on biodistribution of 111In-labeled monoclonal antibody in tumor-bearing mice]

To reduce the high background liver radioactivity in immunoscintigraphy using 111In-labeled monoclonal antibody (In-MoAb), we investigated the effect of diethylenetriaminepentaacetic acid (DPTA) on the in vitro stability of In-MoAb in human serum and the biodistribution of In-MoAb in tumor-bearing mice. In-MoAb was incubated for four days in human serum at 37 degrees C (pH 7.4) in a humidified atmosphere at 5% CO2. The serum sample was analyzed by high performance liquid chromatography every day. Indium-111 gradually transferred from the conjugate to the fraction of transferrin. When DTPA was added to the serum, radioactivity in this fraction disappeared completely and moved to the fraction of DTPA. The daily administration of DTPA to the mice after injection of In-MoAb reduced radioactivity in the normal tissues, especially in the liver after the second day, and improved tumor to normal tissue ratios. Scintigraphic examination also revealed apparent decrease of the liver radioactivity in the mice administered DTPA. These results indicate that 111In dissociated from the conjugate is one of the causes of nonspecific accumulation in the liver and it is possible to decrease this accumulation by the daily administration of DTPA.     

Diverse characteristics of 111In labelled anti-CEA monoclonal antibodies for tumour immunoscintigraphy: radiolabelling, biodistribution and imaging studies in mice with human tumour xenografts

Three monoclonal anti-CEA antibodies, designated 161, 198 (both IgG1) and 228 (IgG2a) have been labelled with 111In via DTPA chelation and assessed for localization in human gastro-intestinal carcinomas as xenografts in athymic nude mice. Following reaction of the antibodies with DTPA anhydride, efficiency of chelation of 111In varied between the antibodies with mean values of 30%, 52% and 62% with 161, 198 and 228 respectively. Gel filtration chromatography with all three labelled antibodies showed radiolabel predominantly coincident with IgG with little radioactivity in either high molecular weight form or as free 111In. However, the efficiency of binding of radiolabelled antibodies to CEA producing tumour cells varied, with maxima of 42%, 65% and 20% for 161, 198 and 228. In vivo, in mice, 111In was excreted at virtually identical rates (half times approx. 12 days) with all three preparations and this was similar to the clearance of indium injected as 111In-indium chloride, but 111In-DTPA was rapidly eliminated (half time approximately 5 h). After injection into mice with CEA producing xenografts of colon carcinoma HT29 and LS174T and gastric carcinoma MKN 45, circulating radiolabel was still predominantly in the form of labelled antibody with little or no detectable immune complexes or 111In labelled transferrin. Tumour localization of all three antibodies was visualized by gamma camera imaging with target: non target ratios of up to 5:1. Dissection of mice with MKN45 gastric carcinoma xenograft showed 16%, 19.5% and 13% of the injected dose of 111In from 161, 198 and 228 antibodies in each g of tumour tissue.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo SPECT/CT imaging of human orthotopic ovarian carcinoma xenografts with 111In-labeled monoclonal antibodies

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 3 (VEGFR-3) are expressed in the tumor area during the progression of ovarian carcinoma. Monoclonal antibodies developed against these receptors are potential diagnostic molecules for in vivo imaging of ovarian carcinoma.

Methods

Biodistribution of the monoclonal antibodies cetuximab against EGFR and mF4-31C1 against VEGFR-3 was studied in nude mice with orthotopic SKOV-3m human ovarian carcinoma xenografts. The biodistribution of ¹¹¹Indium-labeled antibodies was followed up to 48 h postinjection using combined SPECT and CT imaging modality. Organ samples were collected postmortem and specific organ activity was measured. Accumulation of the intravenously injected antibodies in the tumor tissue and lymph nodes was verified using immunohistology.

Results

Imaging studies with SPECT/CT showed clear accumulation of both antibodies into tumor area. The tumor uptake was 8.78±0.74 %ID/g for cetuximab and 5.77±0.62 %ID/g for mF4-31C1 after 48 h postinjection. Cetuximab had lower liver tropism and faster tumor homing rate. In addition, after 48 h two of five tumor-bearing mice showed a clear accumulation of the In-labeled mF4-31C1 at the left axillary area. Both intravenously administered antibodies could also be detected from the tumor sections by immunohistological staining but only mF4-31C1 forms in the lymph nodes.

Conclusion

These results demonstrate the accumulation of EGFR- and VEGFR-3-specific antibodies in orthotopic ovarian carcinoma tumors. Systemically administered they had slow pharmacokinetics which is typical for antibodies. Accumulation of mF4-31C1 antibody in the lymph nodes suggests the remote activation of VEGFR-3 by the primary tumor.     

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.     

Diagnosis of tumors of the parotid gland with anti-CEA immunoscintigraphy

Twenty-nine consecutive patients with a palpable unilateral tumor in the parotid gland region had scintigraphy 22-28 hr after they were injected with 111In-labeled monoclonal anti-carcinoembryonic antigen (CEA) antibody (F023C5). Two patients were imaged at 48 hr also, and one patient was imaged additionally with single-photon emission CT. Twenty-seven of the patients had surgery within 2-3 weeks. The serum CEA concentrations were normal in 27 of 29 patients. Immunoglobulin G human anti-murine-antibody concentrations were elevated in three of 20 patients. Ten patients had scintigraphic findings suggesting a malignant tumor, six of them had histologically proved malignant tumors. The tumors associated with positive immunoscintigrams were stained immunohistochemically with anti-CEA, and four of the malignant tumors were positive in immunohistochemical staining. The results suggest that nonspecific anti-CEA-antibody imaging is helpful in predicting the presence of a malignant tumor in the parotid area. The radioantibody method could provide useful clinical information that has a high negative predictive value.     

A comparative distribution study of 111In-labeled DTPA and TTHA monoclonal antibody conjugates in a choriocarcinoma xenograft model

Conjugates of the chelating agents DTPA and TTHA with a monoclonal anti-HCG were prepared. The tissue distribution of the 111In-labeled conjugates and also 111In-citrate was studied in mice bearing human choriocarcinoma xenografts. The antibody conjugates both gave high liver and spleen radionuclide accumulation. Elevated femur levels were observed for the TTHA conjugate and 111In-citrate. Generally the DTPA conjugate showed the highest tumor/tissue ratios, although its tumor/blood ratio was lower than the other two materials. The results infer that the DTPA conjugate has the greatest utility as an imaging agent but that it would require a background subtraction technique.     

Indium-111-labeled B72.3 monoclonal antibody in the detection and staging of breast cancer: a phase I study

Sixteen patients with primary breast cancer were studied with a pancarcinoma monoclonal antibody B72.3, an IgG1 molecule directed against tumor-associated glycoprotein (TAG-72) present in several tumors. Five millicuries of 111In was used to label 0.2 mg (six patients), or 2 mg (six patients), or 20 mg using the site-directed bifunctional DTPA method (at carbohydrate moiety). Digital, planar, and SPECT images were obtained at 2, 48, 72 and 96 hr when possible. HAMA levels were obtained before the Mab infusion and at 1, 3, and 6 wk postinfusion. Fourteen of 14 known primary breast lesions were detected by imaging (100% sensitivity). Two fibrocystic lesions were negative. Seven of 14 patients had lymph node metastases by histologic methods, but all were missed by radioimmunoscintigraphy. Tumor uptake of Mab ranged 0.00054%-0.0038% of the ID/g. The tumor-to-normal breast tissue ratio was 4.3 +/- 0.91 (mean +/- s.e.m.). Lymph nodes localization of 111In-B72.3 by tissue analysis was similar for tumor-bearing and normal nodes (0.0039 +/- 0.0023 versus 0.0025 +/- 0.0019). Pharmacokinetics revealed mean plasma half-life of 33.3-41.2 hr for the different doses. There was no statistical difference between any of the pharmacokinetic parameters of different doses. HAMA was positive only in 17% of the patients. The study suggests that this antibody has 100% sensitivity for primary breast cancers, but very poor detection rate of metastatic lesions in axillary lymph nodes; thus making it of questionable value in the initial staging process of this disease.     

64Cu-TETA-octreotide as a PET imaging agent for patients with neuroendocrine tumors.

64Cu (half-life, 12.7 h; beta+, 0.653 MeV [17.4%]; beta-, 0.579 MeV [39%]) has shown potential as a radioisotope for PET imaging and radiotherapy. (111)In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe1-octreotide (OC) was developed for imaging somatostatin-receptor-positive tumors using conventional scintigraphy. With the advantages of PET over conventional scintigraphy, an agent for PET imaging of these tumors is desirable. Here, we show that 64Cu-TETA-OC (where TETA is 1,4,8,11-tetraazacyclotetradecane-N,N',N',N'-tetraacetic acid) and PET can be used to detect somatostatin-receptor-positive tumors in humans. METHODS: Eight patients with a history of neuroendocrine tumors (five patients with carcinoid tumors and three patients with islet cell tumors) were imaged by conventional scintigraphy with (111)In-DTPA-OC (204-233 MBq [5.5-6.3 mCi]) and by PET imaging with 64Cu-TETA-OC (111 MBq [3 mCi]). Blood and urine samples were collected for pharmacokinetic analysis. PET images were collected at times ranging from 0 to 36 h after injection, and the absorbed doses to normal organs were determined. RESULTS: In six of the eight patients, cancerous lesions were visible by both (111)In-DTPA-OC SPECT and 64Cu-TETA-OC PET. In one patient, (111)In-DTPA-OC showed mild uptake in a lung lesion that was not detected by 64Cu-TETA-OC PET. In one patient, no tumors were detected by either agent; however, pathologic follow-up indicated that the patient had no tumors. In two patients whose tumors were visualized with (111)In-DTPA-OC and 64Cu-TETA-OC, 64Cu-TETA-OC and PET showed more lesions than (111)In-DTPA-OC. Pharmacokinetic studies showed that 64Cu-TETA-OC was rapidly cleared from the blood and that 59.2% +/- 17.6% of the injected dose was excreted in the urine. Absorbed dose measurements indicated that the bladder wall was the dose-limiting organ. CONCLUSION: The high rate of lesion detection, sensitivity, and favorable dosimetry and pharmacokinetics of 64Cu-TETA-OC indicate that it is a promising radiopharmaceutical for PET imaging of patients with neuroendocrine tumors.     

Bifunctional phage-based pretargeted imaging of human prostate carcinoma

IntroductionTwo-step and three-step pretargeting systems utilizing biotinylated prostate tumor-homing bacteriophage (phage) and ¹¹¹In-radiolabeled streptavidin or biotin were developed for use in cancer radioimaging. The in vivo selected prostate carcinoma-specific phage (G1) displaying up to five copies of the peptide IAGLATPGWSHWLAL was the focus of the present study.MethodsThe ability of G1 phage to extravasate and target prostate tumor cells was investigated using immunohistochemistry. G1 phages were biotinylated, streptavidin was conjugated to diethylenetriaminepentaacetic acid (DTPA) and biotin was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Biodistribution studies and single-photon emission computed tomography (SPECT)/CT imaging of xenografted PC-3 tumors via two-step pretargeted ¹¹¹In-labeled streptavidin and three-step pretargeted ¹¹¹In-labeled biotin were performed in SCID mice to determine the optimal pretargeting method.ResultsThe ability of G1 phage to extravasate the vasculature and bind directly to human PC-3 prostate carcinoma tumor cells in vivo was demonstrated via immunocytochemical analysis. Comparative biodistribution studies of the two-step and three-step pretargeting strategies indicated increased PC-3 human prostate carcinoma tumor uptake in SCID mice of 4.34±0.26 %ID g^?1 at 0.5 h postinjection of ¹¹¹In-radiolabeled biotin (utilized in a three-step protocol) compared to 0.67±0.06 %ID g^?1 at 24 h postinjection of ¹¹¹In radiolabeled streptavidin (employed in a two-step protocol). In vivo SPECT/CT imaging of xenografted PC-3 tumors in SCID mice with the three-step pretargeting method was superior to that of the two-step pretargeting method, and, importantly, blocking studies demonstrated specificity of tumor uptake of ¹¹¹In-labeled biotin in the three-step pretargeting scheme.ConclusionThis study demonstrates the use of multivalent bifunctional phage in a three-step pretargeting system for prostate cancer radioimaging.