Cancer imaging with monoclonal antibodies.
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Antibodies, Monoclonal↗
Biomedical subjects
S M Larson
Publications and source records attributed to S M Larson.
Binding characteristics and biological activity of 17 alpha-[125I]iodovinyl-11 beta-methoxyestradiol, an estrogen receptor-binding radiopharmaceutical, in human breast cancer cells (MCF-7).
17 alpha-[125I]Iodovinyl-11 beta-methoxyestradiol ([125I]MIVE2), a gamma-emitting analogue of estradiol, previously shown to bind to rat uterine estradiol receptor, was studied to determine the binding characteristics and biological activity in human breast cancer cells. In vitro determination of receptor binding by dextran-coated charcoal assays indicates that [125I]-MIVE2 binds specifically and with a high affinity to cytosolic estrogen receptors in the human breast cancer cell line, MCF-7. [3H]Estradiol binds to the receptor with approximately four times the affinity of [125I]-MIVE2 (Kd = 2.55 X 10(-9) M for [125I]MIVE2; Kd = 6.4 X 10(-10) M for [3H]estradiol). Unlabeled MIVE2 produces estrogenic effects similar to those of estradiol such as progesterone receptor induction and increases in thymidine incorporation in MCF-7 cells in culture. Cytosolic progesterone receptor levels were elevated 2.8-fold over control levels by 6 X 10(-9) M MIVE2. Stimulation of thymidine incorporation (approximately 300% above control levels) was observed after exposure to 1 X 10(-9) M MIVE2. Preliminary data show receptor-mediated uptake by the uterus in biodistribution studies in athymic nude mice given injections of [125I] MIVE2 (32-34 microCi). At 4 h, uterus:blood ratios are 20.5 and target tissue:nontarget tissue ratios are 12.9. In light of the fact that this compound can be prepared with a high specific activity, [125I]MIVE2 may have potential as a radiotracer for imaging estrogen receptor-positive breast tumors or metastatic lesions in human breast cancer patients.
Animals↗
A new 111In-bleomycin complex for combined radiotherapy and chemotherapy.
Six days after tumor transplantation three daily intraperitoneal doses of 0.9% NaCl, bleomycin (BLM), or a new 111In-bleomycin complex (BLMC, 15 microCi/g body weight) were administered to glioma-bearing mice. After therapy, tumors in mice treated with 111In-BLMC were smaller than those treated with BLM. Sixteen days after the first injection tumor size for 111In-BLMC-treated mice was 560 (240-1,030) mm3, 1,980 (1,400-3,290) mm3 for BLM (P less than 0.025), and 4,830 (2,580-9,180) mm3 for NaCl (0.1 less than P less than 0.2). Thirteen days after tumor transplantation glioma-bearing mice received single intratumor injection of 0.9% NaCl, BLM, or 111In-BLMC (1.5 mCi, carried by 0.5 mg BLM/g tumor weight). The average tumor size for 111In-BLMC was smaller than that for BLM by a factor of 2.5-3.7. Host weights for these two groups were similar, and morphologic abnormalities were not found in kidney or liver.
Animals↗
Use of I-131 labeled, murine Fab against a high molecular weight antigen of human melanoma: preliminary experience.
High molecular weight antigen (HMWA) is a tumor-associated proteoglycan of human malignant melanoma. I-131 labeled Fab fragments of these specific antibodies were used for preliminary feasibility studies for radioimmunodetection and therapy of human subjects who had inoperable metastatic melanoma. Ten patients received tracer doses of 5-13 mCi (185-481 MBq) of I-131 (anti-HMWA) Fab. All patients (8/8) who had melanoma lesions greater than 1 cm by correlative diagnostic methods had one or more lesions that had localization to tumor of the radiolabeled Fab. In all, 17 of 23 (74%) documented metastases were seen. There were no false positives in this series. Two patients who had avid uptake received potentially radiotherapeutic doses of 142 mCi (5,254 MBq) (one patient) and 181 mCi (6,697 MBq) and 193 (7,141 MBq) (total: 374 mCi or 13,838 MBq) (one patient). For both of these patients, whole body imaging studies showed that the localization of the high dose I-131 Fab was predominantly in tumor. The patient who received the larger dose showed a greater than 50% reduction in the size of pelvic and pericaval nodes, with stabilization of disease at the smaller nodal size for a period of three months. On whole body images, the anti-Fab HMWA appears to be more tumor selective than Fab preparations that target the p97 antigen for melanoma, and there is less uptake in liver.
Animals↗
Prediction of survival in glioma patients by means of positron emission tomography.
The aim of this study was to determine whether positron emission tomography (PET) with fluorine-18 (18F)-2-deoxyglucose (FDG) can be used as a prognostic test in patients with high-grade cerebral gliomas, regardless of the treatment given. Forty-five patients with astrocytoma Grade III or IV were included in this analysis. The mean survival time of patients with tumors exhibiting high glucose utilization as determined by PET-FDG was 5 months, whereas patients with gliomas showing lower glucose utilization had a mean survival period of 19 months. It is postulated that PET-FDG scans reflect the biological behavior of high-grade astrocytomas and may be used to predict the survival time of patients harboring such neoplasms.
Adolescent↗
Monoclonal antibodies in nuclear medicine.
Monoclonal antibodies have been a part of biomedical research for nearly a decade, yet a comparable period of time may be required before radiolabeled monoclonal antibodies come into standard practice in the diagnosis and therapy of human disease. Difficulties in identifying appropriate antigens, developing the optimal antibody species, attaching the most effective radiolabel and choosing the best method of administration all confound present investigations. The problems confronting therapeutic applications are, for the most part, an extension of those associated with diagnostic techniques. Still, there is much well-deserved optimism, and progress in all areas of investigation will ultimately come together to resolve most if not all of these problems. It is inevitable that monoclonal antibodies will have significant impact on the practice of nuclear medicine, and presented here is a review of the basic knowledge as well as an update on the current status of radiolabeled monoclonal antibodies in medicine.
Animals↗
Radiolabeled monoclonal anti-tumor antibodies in diagnosis and therapy.
Clinical work with radiolabeled anti-tumor antibodies has made remarkable progress in the past few years. Still, there is much to be done before these new reagents can have a substantial impact on the practical management of patients. In this discussion, the properties of an "ideal" radiolabeled antibody and important factors for in vivo localization in tumors are reviewed. Potential approaches to improving the localization of currently available "tumor specific" monoclonal antibodies are discussed and examples of patients examined and treated with this method are presented. Experience to date suggests that within the foreseeable future, radiolabeled antibody techniques will become a "genuinely decisive technology".
Antibodies, Monoclonal↗
Melanoma localization in nude mice with monoclonal Fab against p97.
The tumor targeting capacity of monoclonal antibody Fab fragments was explored in nude mice bearing human melanoma xenografts. Radioiodinated Fab 8.2 and 96.5, specific for melanoma-associated antigen p97, were tested in vitro for immunoreactivity and in vivo for tumor localization relative to a co-administered control, Fab 1.4. Fab was cleared rapidly from the blood with a T1/2 of 3-3.5 hr and greater than 90% of the injected radioactivity was excreted by 16 hr. The mean specific Fab in tumor reached a maximum of 3.5% injected dose/g at 4 hr and decreased to 1.5% at 16 hr. Over the same period, the ratio of specific/control Fab in tumor normalized to blood, the localization index, rose from 3 to 25 compared with ratios near unity for all other tissues. The concentration of specific Fab in tumor could be correlated to the amount of Fab protein administered as well as its immunoreactivity.
Animals↗
Imaging of T-cell lymphoma by radiolabelled monoclonal antibody.
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Adult↗
3-[18F]Acetylcyclofoxy: a useful probe for the visualization of opiate receptors in living animals.
A fluoro-analogue of the potent narcotic antagonist, naltrexone, was synthesized and shown to bind with high affinity to opiate receptors in vitro. 3-[18F]acetylcyclofoxy was prepared via a one-step triflate displacement reaction with the positron emitting 18F ion from tetraethylammonium [18F] fluoride. 3-[18F]acetylcyclofoxy accumulation in opiate receptor rich brain regions of both rat and baboon is shown to be completely displaced by the active enantiomer of naloxone [-)-naloxone) while the identical dose of the pharmacologically inert (+)-naloxone has no detectable effect. Moreover, both rat and baboon brain showed the well documented, typical opiate receptor distribution so that basal ganglia and thalamus are clearly visible in the living baboon brain up to 95 min after intravenous injection of 3-[18F] acetylcyclofoxy. We expect that 3-[18F )acetylcyclofoxy will be a useful probe for visualizing opiate receptors in living humans.
Animals↗
Scintigraphy of normal mouse ovaries with monoclonal antibodies to ZP-2, the major zona pellucida protein.
The zona pellucida is an extracellular glycocalyx, made of three sulfated glycoproteins, that surrounds mammalian oocytes. Parenterally administered monoclonal antibodies specific for ZP-2, the most abundant zona protein, localize in the zona pellucida. When labeled with iodine-125, these monoclonal antibodies demonstrate a remarkably high target-to-nontarget tissue ratio and provide clear external radioimaging of ovarian tissue.
Animals↗
A new tumor imaging agent--111In-bleomycin complex. Comparison with 67Ga-citrate and 57Co-bleomycin in tumor-bearing animals.
We have found a new 111In-bleomycin complex (BLMC), which has high affinity to tumor, does not bind to transferrin and is stable in vivo. Distribution in animals bearing glioma, hepatoma, or mammary adenocarcinoma at 48 hours showed: the ratios of tumor to blood, brain, heart, lung, liver, pancreas, stomach, and femur were 1.4-22.4 times as high for 111In-BLMC as for 67Ga-citrate. In mammary adenocarcinoma, 111In-BLMC bound more to viable and 57Co-Bleomycin (BLM) more to necrotic tumor. In viable tumor, the concentration of 111In-BLMC was similar to that of 57Co-BLM. The ratios of tumor to stomach and pancreas were higher, to blood, brain, muscle, heart, and femur were lower for 111In-BLMC than those for 57Co-BLM. The ratios of tumor to lung, liver, spleen, skin, and kidney were similar for the two compounds. Tumors were imaged more distinctly with the new 111In-BLMC and 57Co-BLM than with 67Ga-citrate. 111In-BLMC is promising for tumor imaging.
Animals↗
Nuclear oncology 1984.
New developments in nuclear oncology, based on monoclonal antibodies and position emission tomography measurement of glucose metabolism promise to broaden the range of applications of nuclear medicine methods in the clinical management of patients with tumor. Perhaps of greatest importance, is the prospect of both diagnosing and treating common solid tumors, with the same radiolabeled (monoclonal antibody) pharmaceutical preparation.
Antibodies, Monoclonal↗
Scintigraphic quantification of asynchronous myocardial motion during the left ventricular isovolumic relaxation period: a study in the dog during acute ischemia.
Asynchronous motion of left ventricular myocardium during the period of left ventricular isovolumic relaxation has often been observed in patients with coronary artery disease. Detection and quantitation of this abnormality with noninvasive nuclear tracer methods, however, have not yet been reported. Thus, functional images of regional left ventricular time to minimum counts (or volume), computed from gated blood pool image sequences, were analyzed to detect and quantitate myocardial asynchrony during this interval. The method was tested by comparing regional with global time to minimum counts before and after coronary artery occlusion in the awake dog. After occlusion, minimum counts in the ischemic region occurred later in the cardiac cycle than did global minimum counts (average difference 69 +/- 37 ms, p less than 0.001). Before occlusion, however, minimum counts in the same region occurred at the same moment as global minimum counts (average difference 4 +/- 12 ms, NS). Thus, acute ischemia in dogs produces a pronounced asynchrony in myocardial motion during the earliest moments of diastole. The magnitude of this asynchrony (69 ms) probably corresponds to the length of the global isovolumic relaxation period in these animals after occlusion. This method might be useful in detecting and quantitating isovolumic asynchrony in ischemia and changes in this asynchrony with therapy (verapamil therapy, for example).
Animals↗
Radioimmunodetection and radioimmunotherapy.
The development of monoclonal antibodies that recognize tumor-associated antigens has led to significantly greater practical possibilities for producing highly specific radiolabeled antibodies for diagnosis and therapy of human tumors. A number of problems remain before this technique will be ready for routine clinical application however. Achieving the high target to background ratio that are predicted on theoretical grounds is a major challenge in cancer investigation.
Antibodies, Monoclonal↗
Radioimmunoscintigraphy of human colon cancer xenografts in mice with radioiodinated monoclonal antibody B72.3.
Monoclonal antibody B72.3 reacts with a tumor-associated antigen that is found on human breast and colon carcinomas in significantly higher concentration than in normal adult tissues. Intact B72.3 IgG was labeled with I-131 or I-125 and injected into athymic mice bearing xenografts of human colon cancer. Whole-body scintiphotos obtained with a pinhole collimator demonstrated tumor localization within 24 hr after intravenous administration, and the tumor-to-background ratio rose continuously for at least 14 days. Progressive antibody accumulation was observed in the tumor during the first 3 days, but no significant normal organ localization was observed at any time. No localization was seen in control tumors, a human melanoma xenograft that lacks the antigen recognized by B72.3. The pharmacokinetics of this antibody in tumor-bearing mice suggest that I-131 B72.3 may be useful for radioimmunotherapy as well as radioimmunoscintigraphy of colon cancer in man.
Adenocarcinoma↗
Prolonged binding of a radiolabeled monoclonal antibody (B72.3) used for the in situ radioimmunodetection of human colon carcinoma xenografts.
Monoclonal antibody B72.3 binds to a glycoprotein complex with a molecular weight of 220,000 to 400,000. B72.3 reacts with approximately 50% of human mammary carcinomas and to 80% of the colon carcinomas tested but does not react appreciably with normal mammary tissue, with normal colon, or to a variety of normal adult human tissues tested using immunohistochemical techniques. B72.3 immunoglobulin G was purified and radiolabeled with 125I without significant loss in its reactivity to tumor extracts. The radiolabeled B72.3 immunoglobulin G was shown to efficiently localize human colon carcinoma xenografts in athymic mice. Tumor:tissue ratios of the localized antibody rose over the 7-day period studied, with tumor:liver, tumor:spleen, or tumor:kidney ratios of approximately 18:1 at Day 7 and a tumor:blood ratio of approximately 5:1 at Day 7. Tumor:muscle or tumor:brain ratios rose to over 100:1. The amount of radioactivity in the tumor increased for the first 2 days postinoculation of antibody and stayed constant over a 19-day period of study. Thus, there was no appreciable loss of radioiodine from the tumor over the study interval. No localization was seen in mice bearing a B72.3 antigen-negative human melanoma xenograft or with an isotype-identical control immunoglobulin G in mice bearing colon tumor xenografts. Gamma camera imaging with a pinhole collimator confirmed the ability of the radiolabeled antibody to detect the presence of colon carcinoma xenografts less than 0.5 cm in diameter over a 19-day period. The potential use of this system as a model for radioimmunotherapy will be discussed.
Animals↗
Diagnosis of and therapy for solid tumors with radiolabeled antibodies and immune fragments.
Antibodies which are directed against human tumor-associated antigens can potentially be used as carriers of radioactivity for in vivo diagnosis (radioimmunodetection) or treatment (radioimmunotherapy) of solid tumors, including colon, hepatoma, cholangiocarcinoma, and melanoma. Murine monoclonal antibodies (MOAB), produced by the hybridoma technique of Kohler and Milstein, are replacing conventional heterosera as sources of antibodies, because MOAB can be produced in large quantities as reproducible reagents with homogeneous binding properties. We have studied human melanoma using MOAB IgG and Fab fragments that recognize the human melanoma-associated antigens p97 and "high-molecular-weight antigen." Both antigens are found in the membrane of melanomas at much larger concentrations than in normal adult tissues. We have performed radioimmunodetection studies with whole immunoglobulin and have detected 88% of lesions greater than 1.5 cm. We have used Fab fragments for radioimmunotherapy and have found that large doses of radiolabeled antibodies (up to 342 mCi) can be repetitively given to patients without excessive end-organ toxicity. Two of three patients treated with high-dose radiolabeled antimelanoma Fab showed an effect from the treatment. Although both technical and biologic problems remain, the use of radiolabeled antibodies that are directed against tumor-associated antigens holds future promise as a new therapeutic approach to solid tumors that are resistant to conventional therapy.
Animals↗