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PubMed1993

The coming of age of cancer radioimmunoconjugates.

Great progress in imaging and therapy with radioimmunoconjugates was discussed at the fourth conference on radioimmunodetection and radioimmunotherapy of cancer. Monoclonal antibody-based cancer imaging agents are awaiting marketing approval and newer, potentially improved forms are in development. Tumor responses to radioimmunoconjugates are also being reported in increasing numbers, this is especially so with radiosensitive tumors and in regional or direct applications.

Animals↗
PubMed1995

Radiolabeled monoclonal antibodies.

Monoclonal antibodies (MoAbs) are biologically engineered proteins designed to bind to antigens emanating from tumor cells. Selected radioactive isotopes are fused with MoAbs to allow radioimmunodetection of external imaging of metastatic deposits in patients with colon cancer. For the past 10 years, radiolabeled MoAbs have improved tumor localization techniques and influenced the clinical management of surgical patients. Intraoperatively, surgeons use appropriately shielded, handheld, gamma detection probes to locate radiolabeled MoAbs and corresponding colon cancers (ie, residual, recurrent tumors). Using gamma detection probes intraoperatively, surgeons can localize nonpalpable occult tumors and disease not suspected from external antibody scans or other traditional diagnostic methods. This success confirms the need for complete tumor resections, thorough scanning of entire tumor beds, and ex vivo scanning of surgical specimens to assess for potential nodal metastases.

Animals↗
PubMed1993

Clinical applications of indium-111-labeled monoclonal antibody imaging in colorectal cancer patients.

During the past two decades, the in vivo application of monoclonal antibodies (MoAbs) in cancer diagnosis and therapy have been widely studied. This can be related to three main factors: (1) dramatic improvement in monoclonal antibody production, revolutionized by Kohler and Milstein; (2) improvement in radioisotopes and monoclonal antibody conjugation procedure and further simplification and ease of use of these procedures; and (3) the apparent safety of single or, in selected cases, multiple administration of MoAbs to humans. The development of radioimmunoscintigraphy or radioimmunodetection has added a significant new dimension to nuclear imaging, and it is very likely to broaden our approach to diagnosis and perhaps therapy of malignant diseases. The indications and limitation of radioimmunoscintigraphy must be clearly outlined to the referring oncologists and surgeons. The unique capability of radiolabeled MoAbs in detecting occult disease, upstaging patients, and, most importantly, changing patient management must be emphasized.

Adult↗
PubMed1993

Current status of cancer immunodetection with radiolabeled human monoclonal antibodies.

The use of radiolabeled murine monoclonal antibodies (MoAbs) for cancer immunodetection has been limited by the development of human antimouse antibodies (HAMA). Human monoclonal antibodies do not elicit a significant human antihuman (HAHA) response. The generation and production of human monoclonal antibodies met with technical difficulties that resulted in delaying their clinical testing. Human monoclonal antibodies of all isotypes have been obtained. Most were immunoglobulin (Ig) M directed against intracellular antigens. Two antibodies, 16.88 (IgM) and 88BV59 (IgG3k), recognize different epitopes on a tumor-associated antigen, CTA 16.88, homologous to cytokeratins 8, 18, and 19. CTA 16.88 is expressed by most epithelial-derived tumors including carcinomas of the colon, pancreas, breast, ovary, and lung. The in vivo targeting by these antibodies is related to their localization in nonnecrotic areas of tumors. Repeated administration of 16.88 over 5 weeks to a cumulative dose of 1,000 mg did not elicit a HAHA response. Two of 53 patients developed a low titer of HAHA 1 to 3 months after a single administration of 88BV59. Planar imaging of colorectal cancer with Iodine-131 (131I)-16.88 was positive in two studies in 9 of 12 and 16 of 20 patients preselected by immunohistochemistry. Tumors less than 2 cm in diameter are usually not detected. The lack of immunogenicity and long tumor residence time (average = 17 days) makes 16.88 a good candidate for therapy. Radioimmunlymphoscintigraphy with indium-111 (111In)-LiLo-16.88 administered by an intramammary route was used in the presurgical staging of primary breast cancer. The negative predictive value of lymph node metastases for tumors less than 3 cm was 90.5%. Planar and single photon emission computed tomography imaging of colorectal carcinoma with technetium-99m (99mTc) 88BV59 was compared with computed tomography (CT) scan in 36 surgical patients. The antibody scan was more sensitive than the CT scan in detecting abdominal and pelvic tumors: 68% versus 40% (P < .05). The combination of antibody scan and CT scan was superior to CT scan alone: 80% versus 40% (P < .01). Lesions as small as 0.5 cm in diameter were detected by antibody scan. The CT scan appears superior to the antibody scan for liver metastases. Patients with a high serum titer of HAMA from previous exposure to murine antibodies were successfully imaged. Antibody scans obtained with 99mTc-88BV59 have imaging characteristics similar to murine antibody scans obtained with radiolabeled IgGs. The absence or weak immunogenicity of the human monoclonal antibodies makes them good candidates for radioimmunodetection and radioimmunotherapy.

Breast Neoplasms↗
PubMed1998

Biodistribution and localization of radiolabeled NR-LU-10 Fab fragment in human breast cancer xenografts.

Radioimmunodetection, which takes advantage of tumor-specific or tumor-associated radio-labeled monoclonal antibodies or other biologic molecules to diagnose the extent of disease in cancer patients, has been of limited use in studies to date in patients with breast cancer. The difficulty is in finding an antibody that is both sensitive and specific enough to localize in breast tumors. This study undertook immunohistochemical and in vivo evaluation of tumor localization and biodistribution of NR-LU-10 Fab (antibody fragment) in breast tumors to determine its ability to bind selectively to malignant tissue. NR-LU-10 Fab recognizes a pancarcinoma glycoprotein antigen found on tumors of epithelial cell origin. NR-LU-10 Fab reacted with 6/6 (100%) breast cancer cell lines and 14/16 (87.5%) breast tumors with varying degrees of immunostaining intensities. Athymic mice bearing ZR-75-1 breast cancer xenografts were injected with 125I-labeled NR-LU-10 Fab (12 microg/5 microCi) and sacrificed at fixed time intervals. These studies demonstrated the highest tumor uptake of labeled Fab at 12 h postinjection (4.58+/-1.59% of injected dose/gram [% ID/g] of tissue); this gradually decreased to 0.13+/-0.05% ID/g of tissue by 72 h postinjection of the radiolabeled Fab. Biolocalization to normal tissues was as predicted for a Fab fragment; i.e., initially high in clearance organs (kidney), followed by rapid clearance over the 72-h test period. NR-LU-10 Fab displays adequate breast tumor localization with minimal biolocalization to normal tissues, thus supporting its potential use in radioimmunoscintigraphy and the RIGS system (radioimmunoguided surgery).

Animals↗
PubMed1996

Different biodistribution of 99mTc-labelled chimeric mouse-human monoclonal antibody between athymic mice model and human.

Biodistribution of chimeric mouse/human monoclonal antibody against non-specific cross-reacting antigen (chNCA Ab) was studied in athymic mice and patients with metastatic bone disease. 99mTc-chNCA Ab showed a high labelling efficiency, stability and also a high binding ratio to human granulocytes. Since NCA showed cross-reactivity with carcinoembryonic antigen (CEA), animal experiments showed that 99mTc-chNCA Ab was accumulated in the xenografted tumour which expressed CEA, suggesting the preserved immunoreactivity of labelled materials. In the clinical study, injected 99mTc-chNCA Ab formed a high molecular weight complex immediately after intravenous administration and was trapped mainly in liver. The first-phase plasma half-life was 6.4 +/- 1.1 min. None of the patients showed adverse reaction or human antimurine or anti-chimeric antibody in their serum. 99mTc-chNCA Ab demonstrated remarkably different biodistribution between patients and the animal model and showed different pharmacokinetics from other murine and chimeric Abs reported previously. For safety HPLC analysis should be performed before clinical radioimmunodetection or radioimmunotherapy by incubating radiolabelled MAb with human serum under strict conditions.

Aged↗
PubMed2004

Imaging and therapy of tumors induced to express somatostatin receptor by gene transfer using radiolabeled peptides and single chain antibody constructs.

The fields of radioimmunodetection and radioimmunotherapy began with an initial paradigm that a targeting molecule (eg, antibody) carrying a radioisotope had the potential of selectively imaging and delivering a therapeutic dose of radiation to tumor sites. A second paradigm was developed in which injection of the targeting molecule was separated from injection of a short-lived radioisotope-labeled ligand (so-called "pretargeting strategy"). This strategy has improved radioisotope delivery to tumors in animal models, enhanced radioimmune imaging in man, and therapeutic trials are in an early phase. We proposed a third paradigm to achieve radioisotopic localization at tumor sites by inducing tumor cells to synthesize a membrane expressed receptor with a high affinity for infused radiolabeled ligands. The use of gene transfer technology to induce expression of high affinity membrane receptors can enhance the specificity of radioligand localization, while the use of radioisotopes with the ability to deliver radiation damage across several cell diameters will compensate for less than perfect transduction efficiency. This approach was termed "Genetic Radioisotope Targeting Strategy." Using this strategy, induction of high levels of gastrin releasing peptide receptor or human somatostatin receptor subtype 2 expression and selective tumor uptake of radiolabeled peptides was achieved. The advantages of the genetic transduction approach are (1) constitutive expression of a tumor-associated antigen/receptor is not required; (2) tumor cells are altered to express a new target receptor or increased quantities of an existing receptor at levels that may significantly improve tumor targeting of radiolabeled ligands compared with normal tissues; (3) gene transfer can be achieved by intratumoral or regional injection of gene vectors; (4) it is feasible to target adenovirus vectors to receptors overexpressed on tumor cells by modifying adenoviral tropism (binding) so that the virus will be targeted specifically to the desired tumor; and (5) it is possible to coexpress the receptor gene and a therapeutic gene, such as cytosine deaminase, for molecular prodrug therapy to produce an enhanced therapeutic effect.

Animals↗
PubMed1996

Cloning and expression of cDNAs encoding the variable domains of the antibreast carcinoma antibody Mc5.

Mc5, a murine monoclonal antibody that binds to human breast epithelial mucin (BEM), has been shown to be a promising reagent in the diagnosis of breast cancer. We have cloned cDNAs encoding both variable regions of Mc5 (VL and VH) as well as the CL and CH1 constant regions. Mc5 is an IgG1, kappa antibody. We have constructed an IgG1, kappa human/mouse chimeric antibody (by inserting the murine VH and VL-encoding cDNAs into plasmids encoding human constant domains), and expressed it in SP2/0-Ag14 mouse myeloma cells. The affinity of chimeric Mc5 (chMc5) for BEM is 4.4 x 10(8) M-1. Mc5 binds BEM with an affinity constant of 2.8 x 10(8) M-1. Purified chMc5 and purified Mc5 gave similar competition curves when tested against either 125I-labeled Mc5 or 125I-labeled chMc5 for binding to BEM in a competition radioimmunodetection format. Additionally, chMc5 used in breast carcinoma tissue staining stained as well as the original Mc5.

Amino Acid Sequence↗
PubMed1991

SPECT anti-CEA monoclonal antibody detection of occult colorectal carcinoma metastases.

Radioimmunodetection (RAID) using Tc-99m labeled Fab' fragments of the anti-CEA monoclonal antibody IMMU-4 was performed in a 68-year-old man for preoperative evaluation of colonic metastases. Planar images at 3 and 18 hours showed uptake within known metastases in the left lobe of the liver that had been observed with CT and at surgery during the preceding month. SPECT images at 3 hours demonstrated two additional unsuspected lesions. All sites were surgically confirmed the following day using intraoperative sonographic guidance, with the smallest occult lesion measuring only 6 x 9 mm. This case illustrates the limitations of CT and surgery, the potential of RAID for the detection of occult metastases, the increased sensitivity of SPECT over planar images for detecting lesions less than 1 cm in diameter, and the value of intraoperative guidance for small nonpalpable lesions.

Aged↗
PubMed1995

Radiolocalization of pancreatic carcinoma xenografts in nude mice with radiolabeled chimeric Fab fragments of anti-carcinoembryonic antigen monoclonal antibody A10.

Recombinant mouse-human chimeric Fab fragments of anti-carcinoembryonic antigen monoclonal antibody (MAb) A10 react with various GI carcinomas. We tested radiolocalization of pancreatic carcinoma xenografts in nude mice using radiolabeled chimeric A10 Fab fragments, comparing them with murine Fab fragments and parental MAb. For mice injected with chimeric A10 Fab fragments, we obtained significantly higher uptake in tumors than in normal tissues at 24 and 48 h after injection. In addition, tumor/normal tissues labeling ratios for chimeric A10 Fab fragment were significantly greater than those for murine MAb at 24 h postinfusion. However, no significant difference in biodistribution was observed between chimeric and murine Fab fragments. In autoradiography imaging studies, we obtained clearer tumor detection without visible uptake in normal organs for chimeric Fab fragments than for murine MAb. These results suggest that chimeric Fab fragments of A10 could be a potentially useful candidate for radioimmunodetection of pancreatic carcinomas.

Animals↗
PubMed1992

Autoradiographic analysis of radiolabeled anti-carcinoembryonic antigen monoclonal antibody CEA102 in colorectal cancer using computed radiography.

Anti-carcinoembryonic antigen monoclonal antibody (MAb) CEA102 was produced by immunization with purified CEA and the specific accumulation of radiolabeled CEA102 in colorectal cancers was investigated by autoradiography of surgical specimens using Fuji Computed Radiography (FCR). Five patients with colorectal cancer were injected intravenously with 131I-labeled intact CEA102 or its F(ab')2. Primary tumor and liver metastases were successfully detected by external scanning with a gamma camera in 4 cases. Autoradiographic study of the surgical specimens using FCR showed predominant localization of 131I-labeled CEA102 in primary tumors and liver metastases in all cases. Even a small liver metastasis (0.5 cm) was clearly visualized in the autoradiogram by FCR. The pixel distribution curves of the density of the respective tissues in the autoradiograms by FCR showed the heterogeneity of the distribution of administered radiolabeled MAb in individual tumors, but the density of the tumors was higher than that of the normal tissues. In the quantitative distribution analysis of CEA102, the uptake of the primary tumor (mean 1.10%ID/kg) was ten-fold greater than that of the normal colon mucosa (mean 0.10%ID/kg). These results revealed that the application of MAb has great potential in radioimmunodetection as well as in antibody-directed therapy.

Adult↗
PubMed1992

Detection of locally recurrent colorectal cancer with radiolabeled monoclonal antibody H-15.

H-15 (HT-29-15) is an IgG1 mouse monoclonal antibody (mAb) to a cell surface antigen (molecular mass, 200,000 daltons) present on virtually all colorectal cancers and also in normal pancreatic ducts and bile ducts, but not in other normal tissues. The biological distribution and imaging characteristics of iodine-131 (131I)-labeled mAb H-15 were studied in 5 primary colorectal cancer patients and 9 patients with local recurrence of colorectal cancer. H-15 mAb labeled with 0.5-10 mCi of 131I was administered 7 to 8 days before surgery at 4 dose levels, ranging from 0.2 to 6 mg. Selective mAb H-15 localization to tumor tissues was demonstrated in 6 of 12 patients with antigen-positive tumors: in two patients, recurrent tumors were negative to H-15 mAb, although the primary tumors were positive. In six patients with positive radioimaging, tumor:normal tissue ratios ranged from 2.05 to 5.35 and tumor:serum ratios from 1.18 to 2.73. The clarity of images seems to correlate well with the latter ratios. Technetium-99 (99mTc)-albumin blood pool studies in selected cases showed that local recurrence of colorectal cancers was hypovascular, emphasizing the selective localization of mAb H-15 despite poor blood flow distribution in the tumors. The results altogether demonstrated that radioimmunodetection with 131I mAb H-15 is valuable for differentiating recurrent colorectal cancer from granuloma formation after surgery.

Adult↗
PubMed1995

Therapy and imaging of pancreatic carcinoma xenografts with radioiodine-labeled chimeric monoclonal antibody A10 and its Fab fragment.

Recombinant mouse/human chimeric monoclonal antibody A10 (ch-A10) and its Fab fragment (ch-Fab) react with carcinoembryonic antigen on various gastrointestinal carcinomas. We performed biodistribution studies with 125I-labeled ch-A10 and ch-Fab in an antigen-positive human pancreatic carcinoma (BxPC-3) xenograft model. We also evaluated the anti-tumor effect of 131I-labeled ch-A10, and studied the detection of BxPC-3 xenografts with 123I-labeled ch-Fab in whole body scintigraphy. In comparative biodistribution studies, the tumor uptake of 125I-labeled ch-A10 was significantly greater than that of 125I-labeled ch-Fab 24 h post-injection. However, the tumor-to-blood ratio was 46.8 for ch-Fab at 24 h post-injection, while it was only 1.4 for ch-A10. Microautoradiography studies showed that ch-Fab penetrated more uniformly into the tumor nodules than did ch-A10. In mice given a therapeutic dose of 131I-labeled ch-A10, a significant inhibition of tumor growth was seen, while control 131-I-labeled human IgG did not affect tumor growth. Leukocyte toxicity was observed within 3 weeks after injection of 131I-labeled ch-A10, but leukocyte counts recovered to normal levels at 8 weeks post-injection. In whole-body scintigraphy, clear and rapid tumor imaging was obtained with 200 microCi of 123I-labeled ch-Fab 24 h post-injection. These results suggest that radioiodine-labeled chimeric A10 antibodies could potentially be useful candidates for radioimmunotherapy and radioimmunodetection of pancreatic carcinomas.

Adult↗
PubMed1997

Imaging of recurrent intestinal carcinoma with indium-111-labeled anti-carcinoembryonic antigen monoclonal antibody CEA102.

CEA102 is a mouse immunoglobulin G1 monoclonal antibody (mAb) that detects an epitope of carcinoembryonic antigen (CEA). The biodistribution and imaging characteristics of indium-111-labeled (111-In)-mAb CEA102 were studied in 1 primary and 9 extrahepatic recurrent intestinal carcinoma patients. Evaluation included antibody pharmacokinetics and assessment of antibody distribution in surgical specimens, in comparison with whole body imaging using a gamma camera, and imaging with single photon emission computed tomography. Selective mAb CEA102 localization to tumor tissue was demonstrated in 7 patients with tumors over 2 cm in size, and the external images correlated well with the results of surgical inspection, pathological examination, and tissue radioactivity measurements. Tumor:serum ratios ranged from 0.20:1 to 3.22:1, and serial biodistribution study of "regions of interest" also demonstrated a high radioactivity in the tumor. These results indicated the potential exploitability of the 111-In-labeled mAb CEA102 in radioimmunodetection of primary and extrahepatic recurrence of CEA-positive intestinal carcinomas.

Adult↗
PubMed1995

Carcinoembryonic antigen as a target cancer antigen for radiolabeled antibodies: prospects for cancer imaging and therapy.

This paper reviews the development of cancer imaging with radiolabeled antibodies to carcinoembryonic antigen and the current status and challenges for cancer therapy with radiolabeled antibodies. Advances in antibody preparations, choice of isotope and labeling methods, as well as imaging methods have resulted in rapid and sensitive radioimmunodetection agents that can affect the management of cancer patients. Radioimmunotherapy faces other problems, but advances in antibody engineering and control of dose-limiting myelotoxicity may result in reproducible clinical responses similar to the encouraging results being obtained in the radioimmunotherapy of lymphomas.

Animals↗
PubMedDate not supplied

Radioimmunoscintigraphy of tumors autocrine for human met and hepatocyte growth factor/scatter factor.

Inappropriate expression of the c-met-protooncogene product (Met) and/or of its ligand, hepatocyte growth factor/scatter factor (HGF/SF), has been correlated with poor prognosis in a variety of human solid tumors. We are developing animal models for nuclear imaging of Met and HGF/SF expression in tumors in vivo. We radioiodinated a mixture of monoclonal antibodies (MAbs) that bind to human HGF/SF and to the external ligand-binding domain of human Met, and then injected the I-125-MAb mixture intravenously into mice bearing tumors either autocrine for human HGF/SF and human Met or autocrine-paracrine for murine HGF/SF and murine Met. Serial total body gamma camera images were obtained, and regional activity was determined by quantitative region-of-interest (ROI) analysis. Tumors autocrine for human HGF/SF and Met demonstrated significantly more rapid uptake and more rapid clearance of the I-125-MAb mixture than tumors expressing one or both murine homologues, reaching a mean tumor to total body activity ratio of > 0.3 by 1 day postinjection. We conclude that radioimmunodetection of tumors autocrine for human HGF/SF and Met is feasible with an I-125-MAb mixture reactive against the ligand-receptor pair.

Animals↗
PubMedDate not supplied

Preliminary study on immunoscintigraphy of a murine lymphoma using technetium-99M labeled chicken antibody.

AIMS AND BACKGROUND: Radiolabeled antibodies generated against tumor-associated antigens are used for immunoscintigraphy to detect tumors and tumor metastases. Although successful tumor imaging has been achieved using trace-labeled murine monoclonal antibodies, such antibodies often lead to the development of human anti-murine antibodies (HAMA), which limit their subsequent administration for tumor imaging and therapy. It has been reported recently that chicken polyclonal antibodies have high affinity and specificity for the antigen against which they are raised and do not have any immunological cross-reactivity with HAMA. METHODS: The present study deals with immunoscintigraphy of Dalton's lymphoma, an experimental tumor model using chicken antibodies generated against Dalton's lymphoma-associated antigen (DLAA) and labeled with technetium-99m ((99m)Tc). RESULTS: Scintigrams showed specific uptake of the radiolabel resulting in clear tumor images. The radioactivity uptake of the chicken anti-DLAA antibody was about twofold higher than that of the non-specific chicken antibody. CONCLUSIONS: The results demonstrate the potential of chicken antibody for in vivo radioimmunodetection and localization of tumors.

Animals↗