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PubMed1998

Sentinel lymph node mapping opens a new perspective in the surgical management of early-stage breast cancer: a combined approach with vital blue dye lymphatic mapping and radioguided surgery.

Recent studies have demonstrated the possibility of identifying the sentinel lymph node (sN) as a reliable predictor of axillary lymph node status in both cutaneous melanoma and breast cancer. However, some important issues need further definition: (1) optimization of the technique for intraoperative detection of the sN; (2) predictive value of the sN as regards axillary lymph node status, and (3) reliability of intraoperative histology of the sN. We report our experience in sN mapping in patients with Stage I-II breast cancer, with the aim of assessing: (1) the feasibility of lymphatic mapping with a combined approach (vital blue dye lymphatic mapping and radioguided surgery); (2) the agreement of the intraoperative histologic examination of the sN, by means of hematoxylin and eosin staining with final histology, and (3) the accuracy of sN histology as a predictor of axillary lymph node status.

Aged↗
PubMed1998

Sentinel lymph node biopsy and axillary staging of T1-T2 N0 breast cancer: a multicenter study.

From December 1996 to May 1998, 84 T1-T2 NO breast cancer patients were recruited for a multicenter study on the lymphoscintigraphic search of the axillary sentinel lymph node (SLN). The SLN was searched intraoperatively with a sodium iodide hand-held gamma-detecting probe (GDP) and excised before the standard axillary dissection was performed. Lymphoscintigraphy was unsuccessful in 8 of 84 cases (9.5%). In 73 of 76 patients with positive lymphoscintigraphy, SLN were found and excised (96%). The SLN proved to be predictive of axillary status in 71 of 73 cases (97.2%). Thirty of 41 patients had axillary metastases: in 16 cases, the SLN was the only site of the metastases (50%). In two cases, the SLN (reactive) did not match with the axillary status (2 of 63 reactive SLN, 4.6% of "skip" metastases). Age, tumor diameter, and histology seem to have little importance in affecting the predictivity of SLN biopsy. These results demonstrate the applicability of the lymphatic mapping techniques to a multicenter setting.

Axilla↗
PubMed1998

Sentinel node biopsy in patients with cutaneous melanoma.

The role of elective lymph node dissection (ELND) for treatment of cutaneous melanoma is still debated. Initially, lymphatic mapping technique was performed by an intradermic injection of vital blue dye; subsequently, it was improved by the use of radioguided surgery (RGS). Preliminary experience with this technique proved effective for detection of clinical occult lymph node metastasis; it may also enable the surgeon to perform a selective lymph node dissection (SLND) to concentrate on pathologic node-positive patients for the same potential benefits that have been provided by ELND. We performed sentinel node biopsy on 48 patients with stage pT3N0M0 melanoma. Vital blue dye mapping only was carried out on 39 patients; the remaining nine patients had a combined lymphatic mapping with both blue dye and RGS. The sentinel lymph node (SLN) was identified in 46 of 48 patients (95.8%). Ten patients (20.8%) were found to have metastatic melanoma cells in their SLN(s); all these patients underwent SLND of the affected basin. Our findings confirm that the intraoperative lymphatic mapping of the SLN using both blue dye and radiodetection is an appropriate and simple technique for selecting patients who are more likely to benefit from lymph node dissection.

Adolescent↗
PubMed2000

Sentinel lymph node mapping in early-stage breast cancer: technical issues and results with vital blue dye mapping and radioguided surgery.

BACKGROUND AND OBJECTIVES: Axillary lymph node status is the most important prognostic factor in patients with operable breast cancer. Recent studies have demonstrated the possibility of identifying the sentinel lymph node (sN) as a reliable predictor of axillary lymph node status in both cutaneous melanoma and breast cancer. Sentinel lymph node identification proved feasible by either peritumoral dye injection (Patent Blue-V) or radiodetection, with identification rates of 65-97% and 92-98%, respectively. However, some important issues need further definition, namely (a) optimization of the technique for intraoperative detection of the sN, (b) predictive value of the sN with regard to axillary lymph node status, and (c) reliability of intraoperative histology of the sN. We reviewed our experience in sN detection in patients with stage I-II breast cancer to assess the feasibility and accuracy of lymphatic mapping, by vital blue dye or radioguided surgery, and sN histology as a predictor of axillary lymph node status. METHODS: Two groups of patients (55 and 48) were recruited between May 1996 and May 1997 and between October 1997 and February 1998; the patients of the first series underwent vital blue dye lymphatic mapping only, whereas those of the second series had a combined approach with both vital blue dye mapping and radioguided detection of the sN. RESULTS: In the first set of patients, the sN was identified in 36/55 patients (65.4%); sN histology predicted axillary lymph node status with a 77% sensitivity (10/13), a 100% specificity (23/23), an 88.5% negative predictive value (23/26), and an overall 91.5% accuracy (33/36). The sN was the quasi-elective site of lymph node metastases because in clinically N0 patients nodal involvement was 20-fold more likely at histology in sN than in non-sN (30% and 1.5%, respectively). In the second set of patients, 49 lymphadenectomies were performed because 1 patient had bilateral breast cancer; the sN was identified in 45/49 lymphadenectomies (92%). The sN was intraoperatively negative at frozen-section examination in 33 cases, and final histology confirmed the absence of metastases in 31/33 cases (94%), whereas in 2 cases (6%) micrometastases only were detected. Final histology of the sN predicted axillary lymph node status with an 87.5% sensitivity (14/16), a 100% specificity (29/29), a 93.5% negative predictive value (29/31), and an overall 95.5% accuracy (43/45). CONCLUSIONS: Sentinel lymphadenectomy can be better accomplished when both mapping techniques (vital blue dye and radioguided surgery) are used. In this group of patients, agreement of intraoperative histology of the sN with the final diagnosis was 94%, and sN histology accurately predicted axillary lymph node status in 43/45 lymphadenectomy specimens (95.5%) in which an sN was identified.

Adult↗
PubMed2000

Pattern of lymphatic drainage to the sentinel lymph node in breast cancer patients.

BACKGROUND AND OBJECTIVE: We performed a pilot study on 30 consecutive patients undergoing sentinel node (sN) biopsy by radioguided surgery and vital blue dye mapping to determine whether there is a single sN for each breast independent of tumor site or an sN specifically related to the site of the breast neoplasm. METHODS: There were 6 groups of 5 patients; each patient had a subdermal injection of radiotracer on the tumor site plus a second injection of radiotracer that was changed in every subset of patients to test whether modifying the site or the route of injection could have impaired the proper detection of the sN. RESULTS: "False" sN were detected only in patients who had a second injection of radiotracer away from the tumor site; this occurred in 2 of 5 patients (40%) in group I, in 3 of 5 patients (60%) in group II, in all patients in group III, and in 3 of 5 patients (60%) in group IV. The different route of injection (peritumoral or subdermal) always on the tumor site that was tested in groups V and VI did not impair the proper detection of the sN. CONCLUSIONS: Our findings support the hypothesis of a precise topographic correspondence between the primary tumor and its specific sN more than the existence of a first sN in the axillary basin, which indiscriminately drains all quadrants of the breast, like "a neck of a bottle." This should be considered for the proper selection of the injection site of either vital blue dye or radiopharmaceuticals.

Adult↗
PubMed2001

Disaloganglioside GD2 loss following monoclonal antibody therapy is rare in neuroblastoma.

BACKGROUND: Gangliosicle GD2 is abundant on human neuroblastoma (NB). Monoclonal antibody 3F8 targeted to GD2 may have imaging and therapeutic potential. Antigen-negative clones can escape immune-mediated attack leading to clinical resistance or recurrence. PROCEDURE: Among 95 evaluable patients treated intravenously with 3F8 (94 Stage 4, 1 Stage 3), 66 received nonradiolabeled 3F8, 11 received 131-iodine-labeled-3F8 (8-28 mCi/kg) with autologous bone marrow rescue, and 18 received both forms of treatment. Prior to treatment, 90 patients tested positive for GD2 reactivity by bone marrow immunofluorescence (n = 68), tumor immunohistochemistry (n = 20), or diagnostic radioimmunoscintigraphy (n = 2). RESULTS: Of 62 patients who had refractory or recurrent neuroblastoma following 3F8 treatment, 61 (98%) tested positive for GD2 reactivity by bone marrow immunofluorescence (n = 51) or tumor immunohistochemistry (n = 10). The sole tumor that lost GD2 expression underwent phenotypic transformation into a pheochromocytoma-like tumor. CONCLUSIONS: The persistence of GD2 expression in refractory or recurrent NB suggests that complete antigen loss is an uncommon event and cannot account for treatment failure.

Antibodies, Monoclonal↗
PubMed1987

Incidence and clinical significance of neutralizing antibodies in patients receiving recombinant interferon alfa-2a by intramuscular injection.

More than 1600 patients with neoplastic disorders have received recombinant human interferon alfa-2a (Roferon-A, Hoffmann-La Roche, Nutley, NJ) as part of ongoing or completed clinical trials. In this report, the efficacy of interferon alfa-2a therapy was compared with the incidence of antibodies to this interferon in 617 patients who received the drug by intramuscular administration. Antibody measurements were performed using a highly sensitive enzyme immunoassay, and an interferon antiviral neutralization bioassay. Partial or complete remission occurred in 28% (43 of 152) of the antibody-positive patients, and in 24% (112 of 465) of the antibody-negative patients (P = 0.33). The highest incidence of antibody formation occurred among patients with renal cell carcinoma and acquired immune deficiency syndrome (AIDS)-related Kaposi's sarcoma (44% and 34%, respectively). Both the duration of treatment and length of survival were significantly longer for antibody-positive than for antibody-negative patients. No significant intergroup differences emerged for response rates or for time to onset or duration of therapeutic response. When results from the above assays were compared to those used for the detection of antibodies to recombinant interferon alfa-2b (Intron A, Schering-Plough Inc., Kenilworth, NJ), the immunoradiometric assay method was determined to be seriously deficient for determination of antibody incidence. This decreased assay sensitivity may account for the reportedly lower incidence of antibodies to recombinant alfa-2b interferon.

AIDS-Related Opportunistic Infections↗
PubMed1992

Indium-111 monoclonal antibody B72.3 scintigraphy in colorectal cancer. Correlation with computed tomography, surgery, histopathology, immunohistology, and human immune response.

As part of an open-labeled nonrandomized multi-institutional Phase III study, the authors compared the results of In-111 (In-111) B72.3 glycyl-tyrosyl-n-diethylenetriaminepentaacetic acid lysine (GYK-DTPA) monoclonal antibody scintigraphy with computed tomography (CT), surgery, histopathology, immunohistology, and human antibody response in 23 patients with primary colorectal carcinoma. There were no significant adverse reactions to 1 mg of In-111-labeled antibody. Planar imaging identified 16 of 23 primary colon lesions, whereas single photon emission computer tomography (SPECT) imaging identified 21. SPECT also correctly identified lymphatic involvement in four patients. (There were two false-positive results.) Liver metastases were identified with SPECT imaging. Twenty-six percent of patients developed human anti-mouse antibody (HAMA). These preliminary results demonstrate that In-111 B72.3 GYK-DTPA is a safe monoclonal antibody conjugate that has a high sensitivity for identifying primary colorectal cancer. Regional lymphatic and distant liver metastases also can be imaged, but false-positive results can occur.

Adenocarcinoma↗
PubMed1992

Imaging lung cancer by scintigraphy with Indium 111-labeled F(ab')2 fragments of the anticarcinoembryonic antigen monoclonal antibody FO23C5.

BACKGROUND: Anticarcinoembryonic (CEA) monoclonal antibodies are able to react specifically with the antigen and have the potential for the detection of CEA-bearing tumors. METHODS: The authors photoscanned with indium 111 (111In)-labeled F(ab')2 fragments of the murine CEA monoclonal antibody FO23C5 63 patients with a newly diagnosed and pathologically documented bronchogenic carcinoma. Planar dual views of the thorax, abdomen, and brain were acquired between the 24th and 144th hour after the radiotracer injection. Patients had a complete pretreatment workup, which included a routine multiorgan computed tomography (CT) scan, and the determination of the serum and tissue CEA concentration. All patients were followed up clinically and radiologically. Nineteen needle aspirations and biopsies, 23 surgical explorations, and 4 mediastinoscopic studies yielded 121 pathologically documented sites of reference. RESULTS: Fifty-seven of 63 scans were positive for the primary tumor (sensitivity, 0.90). The uptake of the radiotracer correlated significantly with the intensity of tissue CEA expression (Spearman R [Rs], 0.25; P less than 0.05), but not with the serum CEA level or with the histotype. Overall, the sensitivity of the anti-CEA immunoscintigraphy (IS) for the N1, N2, N3, T3, T4, and M1 disease (1987 International Union Against Cancer [UICC] staging classification) was 0.67, 0.64, 0.62, 0.31, 0.29, and 0.86, respectively. Corresponding values of specificity were 0.67, 0.81, 0.90, 1, 1, and 0.93; accuracy values were 0.67, 0.71, 0.85, 0.71, 0.76, and 0.92. The authors limited the analysis to all of the pathologically documented sites and obtained slightly superior values but no meaningful differences. The stage derived from IS readings was correct in 33 patients. The same figure was obtained after an initial clinical workup, which included physical examination, laboratory routine tests, chest radiographs, bronchoscopy, and any diagnostic procedure indicated by those tests. CONCLUSIONS: Anti-CEA FO23C5-F(ab')2 fragments are not yet "magic bullets" for perfect diagnoses; however, their staging potential seems to be remarkable. Technical improvements, single-photo emission CT, and the use of such fragments in combination with other imaging techniques might enable researchers to further improve the current results.

Adult↗
PubMed1993

Clinical evaluation of tumor targeting with a high-affinity, anticarcinoembryonic-antigen-specific, murine monoclonal antibody, MN-14.

BACKGROUND: The authors previously reported that an anticarcinoembryonic antigen antibody against a carcinoembryonic antigen (CEA)-specific epitope is preferred for clinical investigations. They developed a second generation, CEA-specific murine monoclonal antibody (MoAb), MN-14 (IMMU-14), that has a tenfold higher affinity. This report summarizes the initial clinical experience with the new MoAb. METHODS: MN-14 immunoglobulin G (IgG) (0.5-6.0 mg) was labeled with radioactive iodine (I131) (5-80 mCi) and injected into 22 patients with cancer. External scintigraphy was used to determine targeting in patients with low and highly elevated plasma CEA. Quantitative external scintigraphy methods were used to determine organ and tumor clearance rates and absorbed radiation doses. Targeting data were correlated with several factors, including MoAb protein dose, plasma CEA, and relative tumor burden. RESULTS: Despite more than 80% complexation with plasma CEA of more than 500 ng/ml, all known tumor sites were disclosed by external scintigraphy. The overall sensitivity of tumor targeting on a lesion basis was 89%. The residence time in the blood was predicted by body weight (P = 0.05) and the log of plasma CEA (P = 0.043). The absorbed dose to the red marrow and total body could be predicted by the body weight of the patient, but no other factor contributed significantly to the clearance rate or absorbed dose to the organs. Individual tumors received an average dose of 9.3 +/- 6.4 cGy/mCi. The absorbed dose to the tumors was negatively correlated to the weight of the tumor, and the percent uptake in the tumor was positively correlated to the estimated total tumor burden. Patients injected with approximately 5 mg of MN-14 IgG were more likely to have anti-mouse antibodies (HAMA) develop than were patients who were injected with less MoAb. CONCLUSIONS: These results suggest that MN-14 targets tumors effectively, even in the presence of elevated circulating CEA. Additional studies are necessary to determine if an advantage for the higher affinity MN-14 MoAb, compared with the lower affinity NP-4 MoAb, can be appreciated clinically.

Adult↗
PubMed1993

Immunoscintigraphy in primary colorectal cancer.

Immunoscintigraphy is an experimental diagnostic nuclear medicine imaging technique that targets tumor sites with radiolabeled antibodies reactive with tumor-associated antigens. Primary tumors, regional lymph node metastases, and distant metastases have been imaged in patients with colorectal cancer, and United States Food and Drug Administration (FDA) approval of a commercial preparation of radiolabeled murine monoclonal antibodies for diagnostic use in such patients is expected soon. Immunoscintigraphy is complementary to computed tomography (CT) scanning in the evaluation of the abdomen and pelvis in patients with colorectal cancer, and it has the additional capability of serial whole body imaging for detection of distant metastases. However, the clinical utility of immunoscintigraphy is being investigated, and its precise diagnostic role in patients with primary colorectal cancer has not been adequately defined. The management of selected patients at increased risk of regional or distant spread of tumor likely would benefit from detection of occult disease and a change in clinical staging, but the routine use of immunoscintigraphy in the preoperative evaluation of patients with primary colorectal cancer is more problematic. More studies are required to determine whether it should be used to stage all patients before operation or merely be reserved for selected patients at increased risk for metastatic disease.

Colonic Neoplasms↗
PubMed1993

In-111 CYT-103 monoclonal antibody imaging in patients with suspected recurrent colorectal cancer.

Recurrent colorectal cancer is seen in as many as 40% of patients after curative resection. In view of the limitations of endoscopic and cross-sectional imaging, external immunoscintigraphy has been added to the follow-up regimen of patients at high-risk of recurrent disease. The authors investigated the utility of immunoscintigraphy with Indium-111 (In-111) CYT-103 (site specifically labeled conjugate of monoclonal antibody B72.3) in 19 patients with suspected recurrences after previous curative resection of colorectal carcinoma. Local or regional recurrences (4 patients) and liver metastasis (6 patients) were indicated by physical examination and computed tomography (CT), whereas nine patients had occult disease with increasing serum carcinoembryonic antigen (CEA) levels and negative conventional workups. Serum CEA levels were elevated (mean, 22 ng/ml) in all patients. Approximately 4.3 mCi In-111 labeled to 1.0 mg CYT-103 was administered intravenously to each patient. Planar and single photon emission computed tomography (SPECT) imaging were performed 2-5 days after infusion. The final diagnosis of recurrence or metastasis was established in 18 patients by second-look surgery or biopsy. One patient died before exploration. Tumor was identified at the following locations: pelvis (12 patients), abdominal wall (2 patients), retroperitoneum (1 patient), liver (5 patients), and omentum (2 patients). Superiority of monoclonal antibody (MoAb) scan is noted in the detection of pelvic and intraabdominal recurrences (100%) versus CT scan (43%). Liver metastases were identified with equal facility by both modalities. In-111 CYT-103 scan findings influenced the management of 10 (55%) of 18 patients. Surgery was avoided in one patient with disseminated metastases detected by the scan. Correct identification of occult local recurrences was made in six patients. An isolated liver metastasis was confirmed in one patient with equivocal CT scan. Finally, additional intraabdominal lesions were detected in two patients. These results suggest an important and beneficial role for In-111 CYT-103 MoAb imaging in patients with suspected recurrent colorectal carcinomas, particularly in patients in whom cross-sectional imaging is negative; such imaging may prevent patients from undergoing unnecessary surgical exploration.

Adenocarcinoma↗
PubMed1993

Pitfalls in antibody imaging in colorectal cancer.

Monoclonal antibodies against tumor-associated antigens can be conjugated to radionuclides and used to localize tumors in vivo. This technique may be useful in identifying recurrent disease that cannot be demonstrated using conventional studies such as computerized tomography. The literature suggests that the use of antibody fragments and SPECT imaging will increase the diagnostic yield. The choice of radionuclide may vary depending on the region of interest. Factors that influence the success of imaging include the experience of individuals interpreting the scan and the level of tissue antigen expression. Antibodies of murine origin may produce a human antimouse antibody response after imaging, causing allergic responses, interference with subsequent imaging or results of standard in vitro laboratory tests. Finally, false-positive images occur in more than 10% of patients. Current studies in patients with colorectal cancer should focus on determining if changes in management resulting from antibody imaging have a positive effect on either patient survival or quality of life.

Colonic Neoplasms↗
PubMed1993

Monoclonal antibody imaging in patients with colorectal cancer and increasing levels of serum carcinoembryonic antigen. Experience with ZCE-025 and IMMU-4 monoclonal antibodies and proposed directions for clinical trials.

In an effort to identify the site of recurrent colorectal cancer in patients with occult metastasis and increasing serum CEA levels, we conducted two trials using monoclonal antibodies (MoAb) against CEA. The first utilized Indium-111-labeled ZCE-025; an immunoglobulin G1 (IgG1) anticarcinoembryonic antigen (anti-CEA) antibody (Hybritech, San Diego, CA). The second study used Tc-99m-labeled Fab' fragment of IMMU-4 (Immunomedics, Morris Plains, NJ). Eighteen patients were imaged with the ZCE-025 and 14 with the Tc-99m Fab' IMMU-4. True-positive scans, defined as at least one correct correlation of the MoAb scan and surgical/histologic findings, were observed in 12 of 15 patients undergoing exploration or biopsy using the ZCE-025 and 11 of 14 using the IMMU-4. There were no true-negative scans with the ZCE-025 and only 2 of 14 with the IMMU-4. There were 3 false-positive scans with the ZCE-025 and 1 of 14 with IMMU-4. There were no false-negative scans with either ZCE-025 or IMMU-4. Four (31%) of 13 patients undergoing exploration and imaged with ZCE-025 and 5 (36%) of 14 imaged with IMMU-4 had complete tumor resection. Treatment decisions were affected in 3 (16%) of 18 ZCE-025-imaged patients and 3 (21%) of 14 IMMU-4 ones. Two (14%) of 14 patients imaged with IMMU-4 had negative MoAb scans and negative laparotomies. Despite these findings, it is not known whether such early detection and resection will translate into improved survival rates. The authors suggest two randomized studies, one designed to ascertain the role of MoAb added to blind exploratory laparotomy. In that study, patients with increasing CEA levels and a negative workup will be randomized to an exploratory laparotomy preceded by MoAb anti-CEA scans or a straight exploratory laparotomy without the assistance of a MoAb anti-CEA scan. Endpoints will be differences in complete resectability and survival. A second study will examine the merits of blind exploratory laparotomies. In that study, patients with increasing CEA levels and a negative workup would be randomized to MoAb imaging, exploratory laparotomy, and radioimmunoguided surgery, and the other cohort of patients would continue to have conventional radiologic workup. Exploration in this latter group would be performed only when indicated by radiologic or endoscopic studies. The endpoint of the study would compare survival in the two cohorts of patients. These two studies may ultimately settle the debate regarding the correct approach to patients with occult metastatic colorectal cancer and a increasing levels of serum CEA.

Antibodies, Monoclonal↗
PubMed1993

Immunoscintigraphy in patients with colorectal, ovarian, and prostate cancer. Results with site-specific immunoconjugates.

Application of monoclonal antibody (MoAb) technology to cancer management is discussed by reviewing the development and clinical evaluation of two MoAb-based immunoscintigraphic agents (111In-satumomab pendetide [OncoScint CR/OV-In] and 111In-CYT-356; Cytogen Corporation, Princeton, NJ). Both agents were prepared using a site-specific MoAb modification method that preserves the immunoreactivity of the radiolabeled immunoconjugate. 111In-satumomab pendetide is an 111In-labeled conjugate of the murine MoAb B72.3, which is directed to TAG-72, an antigen expressed by the majority of adenocarcinomas. By providing information that complements the results of standard radiographic diagnostic modalities, this imaging agent can aid in the treatment of patients with colorectal or ovarian cancer. Immunoscintigraphy with 111In-satumomab pendetide has been shown to assist in medical-surgical management by detecting occult extrahepatic lesions, clarifying equivocal results of other diagnostic imaging tests, and evaluating the extent and resectability of known tumor lesions. 111In-CYT-356 is an 111In-labeled conjugate of the murine MoAb 7E11-C5.3, which is reactive with prostatic carcinoma, benign prostatic hypertrophy, and, to a lesser extent, normal prostatic tissue. Results of preliminary clinical investigations suggest that 111In-CYT-356 immunoscintigraphy can be useful for the presurgical staging of prostatic carcinoma and for the detection of occult distant disease in patients with negative or equivocal results on standard imaging tests. Results with these site-specifically radiolabeled immunconjugates demonstrate the clinical utility of MoAb-based imaging agents in the treatment of patients with solid tumors.

Antibodies, Monoclonal↗
PubMed1994

Comparative tumor localization of whole immunoglobulin G anticarcinoembryonic antigen monoclonal antibodies IMMU-4 and IMMU-4 F(ab')2 in colorectal cancer patients.

BACKGROUND: Previous studies in the literature have suggested that radiolabeled F(ab')2 fragments might be superior to whole immunoglobulin G (IgG) for imaging and therapy of cancer because of their greater penetration in tumors. To test this hypothesis, the authors compared tumor and normal tissue uptake along with plasma clearance of 125I-labeled monoclonal antibody (MoAb) IMMU-4 whole IgG with its 131I-labeled F(ab')2 fragment. METHODS: Five patients with either liver metastases from colorectal cancer (n = 4) or intact primary tumors (n = 1) received a combination of 125I-IMMU-4 IgG (2 mCi/1 mg) plus 131I-IMMU-4 F(ab')2 (10 mCi/1 mg) as a single 1-hour intravenous infusion on day 1. Serial blood samples were taken for up to 72 hours postinfusion to determine plasma clearance of each MoAb. On days 3-9, patients underwent exploratory laparotomy in which biopsies of tumor as well as normal tissues (liver, normal colon, lymph node, and blood) were obtained. Tissues were weighed and counted in a gamma counter, and the percent of injected dose per kilogram (%ID/kg) of each antibody, along with the radiolocalization index (RI), was computed (RI = %ID/kg tumor.%ID/kg normal tissue). RESULTS: Tumor uptake of both antibodies (2.3 +/- 0.53 %ID/kg) was significantly higher than that of normal tissues (0.56 +/- 0.12; P < 0.001), except for blood (2.8 +/- 0.83), resulting in an RI > or = 3. There were no significant differences in uptake (%ID/g) between F(ab')2 and IgG (F[ab']2 = 2.0 +/- 0.57; IgG = 2.6 +/- 0.94). The mean +/- SD of plasma T1/2 was slightly shorter for F(ab')2 (28.8 +/- 7.2 hours) than for IgG (45.9 +/- 16.7; P = 0.08). CONCLUSION: In short, the biodistribution and pharmacokinetics of IMMU-4 F(ab')2 were comparable to those of IMMU-4-IgG.

Animals↗
PubMed1994

Immunoscintigraphy of colon cancers with the human monoclonal antibody COU-1.

The human monoclonal immunoglobulin M (IgM) antibody, COU-1 is obtained from a human-human hybridoma, which is derived by fusion between a human B-lymphoblastoid cell line and lymphocytes obtained from mesenteric lymph nodes from a patient with colorectal cancer. COU-1 recognizes a 43 kilodaltons intracellularly located cytokeratin-like protein, strongly expressed by adenocarcinoma tissue as compared to normal tissues. In tumor-bearing nude mice, antibody COU-1 labeled with 125I has been shown to accumulate in human colon cancer grafts when compared to human melanoma grafts and the normal mouse tissues. The observed accumulation was sufficient to be detected externally by immunoscintigraphy. Antigen-binding fragments of the antibody were also prepared and were shown to accumulate in colon cancer grafts. Improved tumor to normal tissue ratio was seen with the half-monomeric fragment, and the time required was reduced. In the clinic, five patients with suspected colorectal cancer were given 2 mg of 131I-labeled COU-1. No adverse effects were detected in any of the patients. Planar images were obtained on days 1, 2, 3, 5, and 7 after administration. The best images were obtained on days 5 and 7. Tumors were localized by immunoscintigraphy in four of the patients. Of these patients, surgery revealed that three of them had primary colorectal cancers located in the cecum, the ascending colon, and the rectum, respectively, while one patient had a pancreatic cancer. The smallest lesion observed had a diameter of 3 cm. In one of the patients, otherwise undiagnosed multiple liver metastases were revealed by the immunoscintigraphy and confirmed at surgery. An x-ray of the colon performed on the fifth patient had shown a stricture in the descending colon suspected to be caused by cancer. The tumor scintigraphy showed no accumulation of the antibody. Surgery revealed that the stricture was caused by adherence and not cancer. These findings are encouraging for further studies of this human monoclonal antibody in cancer patients.

Adenocarcinoma↗
PubMed1994

Detection of ovarian cancer by 198Au-labeled human monoclonal antibody.

BACKGROUND: There is no reliable method for the early diagnosis of ovarian cancer. Radiolabeled monoclonal antibodies have potential to assist in early diagnosis, but they are limited by problems that include antibody specificity, stability, and immunoreactivity, as well as patient reactions to the antibodies used. METHODS: Methods were developed to 198Au-label a human monoclonal antibody (TC5 antibody), developed against an ovarian cancer cell surface antigen. Antigen binding sites on the TC5 antibody were protected with sepharose 4B affinity chromatography before 198Au-labeling. The 198Au-labeled TC5 antibody was evaluated with biopsy specimens in a blind study. The immunoreactivity of radiolabeled TC5 antibody also was evaluated in slot-blot experiments with extracts of the biopsy specimens. RESULTS: The 198Au-labeled TC5 antibody had high binding reaction to all biopsy specimens (six of six) pathologically diagnosed as ovarian cancer (serous and endometrioid adenocarcinoma). The radiolabeled TC5 antibody did not bind to any normal (non-neoplastic) specimens (zero in ten), with one exception. One "normal" ovary specimen had high binding of radiolabeled TC5 antibody, and metastatic ovarian cancer was diagnosed 4 months later. The TC5 antibody labeled with 198Au, without protecting antigen-binding sites, did not bind to any biopsy specimens. CONCLUSIONS: The affinity-labeling method was necessary to protect antigen-binding sites and preserve the immunoreactivity of the TC5 antibody. The 198Au-labeling method may be an ideal technique to evaluate monoclonal antibodies in vitro. The TC5 antibody had high sensitivity and specificity for detecting ovarian cancer.

Antibodies, Monoclonal↗