This clinical study was based on experimental results obtained in nude mice grafted with human colon carcinoma, showing that injected 131I-labeled F(ab')2 and Fab fragments from high affinity anti-carcinoembryonic antigen (CEA) monoclonal antibodies (MAb) gave markedly higher ratios of tumor to normal tissue localization than intact MAb. 31 patients with known colorectal carcinoma, including 10 primary tumors, 13 local tumor recurrences, and 21 metastatic involvements, were injected with 123I-labeled F(ab')2 (n = 14) or Fab (n = 17) fragments from MAb anti-CEA. The patients were examined by emission-computerized tomography (ECT) at 6, 24, and sometimes 48 h after injection using a rotating dual head scintillation camera. All 23 primary tumors and local recurrences except one were clearly visualized on at least two sections of different tomographic planes. Interestingly, nine of these patients had almost normal circulating CEA levels, and three of the visualized tumors weighed only 3-5 g. Among 19 known metastatic tumor involvements, 14 were correctly localized by ECT. Two additional liver and several bone metastases were discovered by immunoscintigraphy. Altogether, 86% of the tumor sites were detected, 82% with F(ab')2 and 89% with Fab fragments. The contrast of the tumor images obtained with Fab fragments suggests that this improved method of immunoscintigraphy has the potential to detect early tumor recurrences and thus to increase the survival of patients. The results of this retrospective study, however, should be confirmed in a prospective study before this method can be recommended for the routine diagnosis of cancer.

/pdf/detection-of-colorectal-carcinoma-by-emission-computerized-55d8jchpz9.pdf

Detection of colorectal carcinoma by emission-computerized tomography after injection of 123I-labeled Fab or F(ab')2 fragments from monoclonal anti-carcinoembryonic antigen antibodies.

PURPOSEThis review was conducted to characterize the results of trials of unconjugated monoclonal antibodies in the treatment of cancer. This survey does not cover antibodies conjugated to drugs, isotopes, or toxins.METHODSAn English-language literature search was used to identify reports of trials of unconjugated monoclonal antibodies in patients with cancer.RESULTSMost trials have been pilot or phase I to II in nature. The most encouraging results have been described for various antibodies directed against lymphoma, and for certain monoclonal antibodies that bind to glycolipid antigens on melanoma, sarcoma, and neuroblastoma. Toxicity has not been a major problem with these reagents, but human antimouse antibodies have limited the potential application of murine reagents.CONCLUSIONAt present, there are no unconjugated monoclonal antibodies that have proven therapeutic benefit in hematologic malignancies or solid tumors. The most active areas of current interest relate to antibodies to various growth fac...

Antibodies as cytotoxic therapy.

We previously have reported that radioiodinated anti-tenascin monoclonal antibody 81C6 exhibits therapeutic potential against both s.c. and intracranial human glioma xenografts in athymic mice and rats. Herein we report the selective tumor localization of 131I-labeled 81C6 in patients with gliomas and other intracranial malignancies. Nine patients were simultaneously administered 5–50 mg of 131I-labeled 81C6 and 1–2 mg of 125I-labeled 45.6, an isotype-matched control monoclonal antibody. The blood clearance half-time for 81C6, normalized to that of 45.6 in the same patient, appeared to decrease with 81C6 protein dose. Gamma camera images obtained at 1 to 3 days exhibited increased uptake of 131I in regions corresponding to tumor with varying degrees of contrast to surrounding normal brain. Biopsy specimens of tumor and normal brain were obtained and analyzed histologically for tumor content. The average uptake of 81C6 in tumor ranged from 0.6 to 4.3 × 10-3% of the injected dose per gram. In patients receiving 20–50 mg of 81C6, the average tumor-to-normal-brain ratio was 25:1 with ratios as high as 200:1 seen in some samples. Localization indices were calculated by normalizing the uptake of 81C6 per gram tumor to the uptake of 81C6 per gram blood and dividing by the same ratio for 45.6 control monoclonal antibody. Localization indices for muscle and brain were about 1, in contrast to up to five for tumor. These studies demonstrate that the tumor uptake of 131I-labeled 81C6 in patients with gliomas and other intracranial malignancies is due to specific processes.

https://cancerres.aacrjournals.org/content/canres/49/10/2807.full.pdf

Pharmacokinetics and Tumor Localization of 131I-Labeled Anti-Tenascin Monoclonal Antibody 81C6 in Patients with Gliomas and Other Intracranial Malignancies

Antibody conjugates were prepared by coupling F(ab′)2 or Fab′ fragments of an antibody specific for the human high molecular weight-melanoma associated antigen to Fab′ fragments of an antibody specific for indium-diethylenetriaminepentaacetate complexes. Monovalent and bivalent haptens were synthesized by reacting the dipeptide tyrosyl-lysine with diethylenetriaminepentaacetic cyclic anhydride. In vitro, the antibody conjugate mediated binding of the 111In-labeled haptens to melanoma cells. In vivo, it allowed specific localization of the haptens in A375 tumors. The bivalent hapten exhibited much higher efficiency at targeting 111In onto cells, both in vitro and in vivo. Antibody conjugate and hapten doses (2 µg and 1 pmol, respectively) and the delay between antibody conjugate and tracer injections (24 h) were adjusted to maximize tumor uptake (4% injected dose/g) and tumor to normal tissue contrast (>3) obtained 3 h after injection of the 111In-labeled bivalent hapten. This two-step technique, when compared to direct targeting of 111In-labeled F(ab′)2 fragments, provided lower localization of injected activity into the tumor (× 0.25), but higher tumor/tissue ratios, especially with respect to liver (× 7), spleen (× 8), and kidneys (× 10). In addition, high contrast images were obtained within 3 hours, instead of days. Thus, antibody conjugate-mediated targeting of small bivalent haptens, labeled with short half-life isotopes, is proposed as a general method for improving tumor radioimmunolocalization.

https://cancerres.aacrjournals.org/content/canres/50/11/3445.full.pdf

Targeting of indium 111-labeled bivalent hapten to human melanoma mediated by bispecific monoclonal antibody conjugates: imaging of tumors hosted in nude mice.

BACKGROUND

A large number of monoclonal antibodies (MoAbs) against human tumor cells have been generated and it has been shown that these MoAbs are useful tools in the diagnosis and treatment of cancer patients, as well as in the basic investigation of the oncogenesis and characterization of cancer cells.



METHODS

The 22-1-1 MoAb was established by cell fusion between mouse myeloma cells and spleen cells derived from mice immunized with the human uterine cervical adenocarcinoma cell line, SiSo. The tissue distribution and biologic characteristics of the 22-1-1 antigen (Ag) were examined.



RESULTS

The 22-1-1 Ag was distinct from the known tumor-associated antigens such as YH 206, GA 733, CA 125, carcinoembryonic antigen, and sialyl Lex molecules in an expression pattern in human tumor cell lines. An immunohistochemical study revealed that 22-1-1 Ag was expressed in 87.5% of uterine cervical adenocarcinomas, 66% of uterine endometrial adenocarcinomas, and 58.8% of ovarian carcinomas. Moreover, 22-1-1 Ag was detected in 87.7% of uterine cervical squamous cell carcinomas; however, it was not detected in normal uterine cervical or ovarian tissues, except in uterine endometrial glands, in which its expression was observed at low levels. The 22-1-1 Ag was secreted into cell culture supernatant fluids and was also detected in the vaginal discharges of uterine cervical carcinoma patients. The antigenic epitope of 22-1-1 Ag was shown to be a protein with a molecular weight of 78 kilodaltons using sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis.



CONCLUSIONS

The 22-1-1 MoAb reactive to a novel tumor-associated antigen was generated. This Ag was expressed in cancer cells derived mainly from the uterus and ovary. Moreover, 22-1-1 Ag was secreted in the vaginal discharges of uterine cervical carcinoma patients. 22-1-1 MoAb is a potential tool for the study of oncogenesis and the management of cancer patients. Cancer 1996; 77:1501-9.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/%28SICI%291097-0142%2819960415%2977%3A8%3C1501%3A%3AAID-CNCR12%3E3.0.CO%3B2-3

A novel tumor-associated antigen expressed in human uterine and ovarian carcinomas

The murine 96.5 monoclonal antimelanoma antibody (MoAb) was labeled with In-111, and 1-20 mg were administered to 21 patients who had proved or suspected melanoma metastases. One patient was studied twice. In four patients, unlabeled 96.5 MoAb was administered prior to the radiopharmaceutical. All of the patients tolerated the procedure without toxicity regardless of the mass of MoAb administered. The scans were interpreted by two observers, one with full knowledge, the other with no knowledge of the cases. Increasing the MoAb mass or preinfusing unlabeled MoAb prior to the administration of In-111 MoAb resulted in a prolongation of the serum half time, and appeared to improve tumor detection. Lesions were best seen at 72 hours after infusion or later. In all patients who had metastatic disease, at least one tumor site was apparent. Fifty-six per cent of known lesions 1.5 cm or greater in size were detected by the physician who had knowledge of the cases when data from all doses were considered. There wer...

Radioimmunodetection of melanoma utilizing In-111 96.5 monoclonal antibody: a preliminary report.

• Even with the advancement of radiologic techniques, metastatic cancers can still be difficult to detect. In this study, 48 patients suspected of having occult metastases were studied by radioimmunodetection following the administration of 92.5 to 181.3 MBq of indium 111–labeled monoclonal anticarcinoembryonic antigen antibody. All but seven patients were thought to have metastatic colorectal carcinoma. In the majority of cases, physical examinations and computed tomographic scans had failed to detect a lesion. At least one lesion that was later proved to exist was detected in 34 of the 50 studies performed on these patients. Seven of eight patients with normal radioimmunodetection scans remain free of disease. One hundred one sites were detected overall; 60 were considered true-positive sites and 27 false-positive sites. Fourteen sites remained in question. Nineteen false-negative sites occurred. Radioimmunoimaging appears valuable for the detection of occult cancer where standard, noninterventional techniques have failed to detect the suspected disease. (Arch Surg. 1992;127:1094-1100)

Detection of occult tumor using indium 111-labeled anticarcinoembryonic antigen antibodies.

We infused 111-Indium conjugated murine monoclonal antibodies into 37 patients with various malignancies. One patient with breast cancer received a human IgM conjugate. At least one known site of tumor was imaged in 75% of patients, and 50% of all known lesions were successfully imaged. In 6 patients, lesions were detected which had not been previously appreciated. There was no toxicity except in patients in whom the antibody cross-reacted with circulating cells. Isotope was concentrated nonspecifically in the liver of all patients. These studies confirm the feasibility of immunoscintigraphy, but emphasize several problem areas for radioimmunotherapy.

Immunoscintigraphy with 111-Indium Conjugated Monoclonal Antibodies

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Radioimmunodetection of melanoma utilizing In-111 96.5 monoclonal antibody: a preliminary report.

Detection of occult tumor using indium 111-labeled anticarcinoembryonic antigen antibodies.

Immunoscintigraphy with 111-Indium Conjugated Monoclonal Antibodies