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Biomedical subjects

I Hellström

Publications and source records attributed to I Hellström.

At least 127 records · Page 7Linked to original sources
PubMed1985

Pilot trial of murine monoclonal antibodies in patients with advanced melanoma.

We have performed a pilot trial with two murine monoclonal antibodies (MAbs) directed against two surface membrane antigens, p97 (MAb 96.5) and a proteoglycan antigen (MAb 48.7) primarily expressed in human melanoma. Five patients with disseminated melanoma were studied, all of whom had multiple cutaneous metastases. Four patients received 212 mg each of antibodies 96.5 and 48.7, and one patient received 424 mg of antibody 96.5 alone. MAbs were administered in escalating doses over ten days in four patients and over six days in one patient. There was no clear treatment-related toxicity. Immunohistologic studies on biopsies taken two to 240 hours after treatment showed extensive binding of murine immunoglobulin to melanoma cells, but not to normal cells in the same section. The intensity of antibody binding was uniform across the diameter of the tumor nodules. In two patients, no murine immunoglobulin was detected in biopsies taken ten days after the last treatment. The mean initial elimination half-life (T1/2) of infused MAbs was 40.5 hours in two patients who received a combination of both antibodies and 53.0 hours in a third patient who received only antibody 96.5; none of these patients had previously been exposed to mouse immunoglobulin. The elimination T1/2 was 21 hours in a fourth patient, who three months previously had tumor imaging with 2-mg radiolabeled antigen-binding fragments (Fab) prepared from antibody 48.7. Serum from this patient appeared to contain anti-idiotypic antibodies which specifically bound Fabs of antibody 48.7. Three other patients also developed human anti-mouse antibodies. There were no objective tumor regressions, and no histologic changes were noted on biopsy.

Adult↗
PubMed1985

Monoclonal antibodies to cell surface antigens shared by chemically induced mouse bladder carcinomas.

Rats were immunized with cultured cells from chemically induced transitional cell carcinomas of the mouse urinary bladder, and their spleen cells were hybridized with NS-1 mouse myeloma cells. Following initial screening of antibodies made by hybridoma clones, the tissue distribution of antigens defined by the antibodies was established by using a peroxidase-antiperoxidase technique with frozen sections of a variety of mouse tumors, as well as normal adult and embryonic tissues. Two antibodies were identified which detected antigens with bladder carcinoma specificity. One antibody (3B12) reacted weakly with epithelial cells from several sources, including normal bladder, while the second antibody (6.10), which bound strongly to bladder carcinoma cells, was negative on bladder epithelium and bound (weakly) to only a small fraction of all epithelial cells tested except for epidermal cells and periosteum from embryos. Both antibodies should be useful to assess the immunotherapeutic and immunoprophylactic effects of monoclonal antibodies to tumor-type specific oncofetal antigens.

Animals↗
PubMed1985

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↗
PubMed1984

Amphipathic lipid-bound protein antigens in mouse bladder carcinomas detected by a monoclonal antibody.

We have found organic solvent soluble proteins that contain tightly bound fatty acids. They were demonstrated in mouse bladder carcinomas by a monoclonal rat antibody, 33E7C. The antigens recognized by antibody 33E7C copurified with lipids when extracted from bladder carcinomas with a mixture of chloroform-methanol. The antigens remained in the chloroform phase after solvent partition with water. Chromatographic analysis using an alpha-hydroxy-propylated Sephadex G-50 (LH60) column led to the isolation of a group of proteins binding to antibody 33E7C. Four proteins (10K, 18K, 25K, and 40K daltons) were found on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) after radioimmunoprecipitation with antibody 33E7C. After preparative SDS-PAGE, the purified antigens were soluble in both water and a mixture of chloroform-methanol (2:1) but were freed from phospholipids and glycolipids. The antigens have been characterized by the presence of tightly bound fatty acids with the following findings: (1) They were metabolically colabeled by incubating bladder carcinoma cells with [9,10-3H]palmitic acid and [14C]leucine, followed by radioimmunoprecipitation assay and by SDS-PAGE. (2) After hydrolysis of proteins in NaOH-methanol, [3H]palmitic acid methyl ester was separated from the 40K and 18K proteins by thin-layer chromatography.

Animals↗
PubMed1984

Diagnostic and therapeutic use of monoclonal antibodies to human tumor antigens.

Monoclonal antibodies have been obtained to various differentiation antigens that are more strongly expressed on tumor cells than on normal cells from the adult host, some of these antigens are relatively specific for tumors of a given type, e.g. melanoma. Monoclonal anti-tumor antibodies offer strong promise for clinical use, initially for tumor diagnosis and, ultimately, also for therapy.

Antibodies, Monoclonal↗
PubMed1984

Induction of immunity to a human tumor marker by in vivo administration of anti-idiotypic antibodies in mice.

Anti-idiotypic antibodies are described that were raised against murine monoclonal antibody 8.2, an antibody specific for a human melanoma-associated cell surface marker called p97. The 8.2 idiotopes recognized by this anti-idiotypic antiserum are binding site-associated and are shared by other monoclonal anti-p97 antibodies with the same specificity as antibody 8.2. Mice immunized with the anti-idiotype demonstrate delayed-type hypersensitivity reactions when challenged with melanoma (p97-positive) tumor cells.

Animals↗
PubMed1984

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↗
PubMed1984

High-level iodination of monoclonal antibody fragments for radiotherapy.

Two different murine monoclonal antibody Fab fragments specific for p97, a melanoma-associated antigen, were labeled with I-131 at high activity levels without excessive chemical damage. Up to 20 mg of Fab were labeled with up to 300 mCi of I-131 using the chloramine-T method and large working volumes at room temperature. As much as 90% of the initial activity was recovered as labeled product. The labeled Fabs varied in their sensitivity to radioiodination damage, as measured by an in vitro cell-binding assay. Radioiodination was performed safely using a remote iodination apparatus. The final product was of radiopharmaceutical quality suitable for clinical diagnosis and experimental radiotherapy in humans.

Animals↗
PubMed1983

Melanoma-associated antigen p97 continues to be expressed after prolonged exposure of cells to specific antibody.

p97, a 97,000 molecular weight cell surface glycoprotein associated with human melanoma, has attracted attention as a possible target for tumor therapy. Melanoma cells were grown overnight in the presence of IgG2a or IgG1 monoclonal antibodies specific for p97, and then exposed to complement and also tested for binding of monoclonal antibodies specific for other epitopes of p97. The results indicated that melanoma cells continued to express p97 after prolonged exposure to specific antibody, a prerequisite for many therapeutic applications.

Antibodies, Monoclonal↗
PubMed1983

Suppressor mechanisms in tumor immunity.

There are many parallels between T cell-mediated suppression of tumor immunity and suppression of immune responses to haptens and polypeptides. We propose a cell interaction model which takes this into account and outlines a regulatory pathway for suppression of immunity to tumor antigens. Free antigen or antigen/antibody complexes trigger an inducer T cell subset, Tsi, which is tumor-specific. This cell activates a non-immune T cell population, pre Tse, to generate effector suppressor cells, Tse. The Tse are specific for either the idiotype of Tsi or for antigen complexed with a soluble factor made by the Tsi, but the suppression they mediate is antigenically nonspecific. Tumor antigen-specific suppressor factors, TsF, play a major role in the communication between different suppressor cells. Characterization of polyclonal and monoclonal factors produced by Tsi, called TsFi, indicates that they both bind to tumor antigen and contain tumor-specific (idiotypic?) determinants.

Animals↗
PubMed1983

Localization of melanoma-associated antigen p97 in cultured human melanoma, as visualized by light and electron microscopy.

The expression of a human melanoma-associated antigen, p97, in cultured melanoma cells was investigated using a modification of the Sternberger peroxidase-antiperoxidase (PAP) technique. Explant cultures of two skin melanomas were found to consist of a mixture of cells, some positive and some negative, for the expression of p97. From two other melanomas two cell lines were newly established. All cells from these lines expressed detectable p97 over a period up to 18 months. With the cell lines and the explant cultures we have initiated an investigation of the expression of p97 at the ultrastructural level, using the PAP technique. Antigen expression was detected as a continuous, strongly stained band at the cell surface of the melanoma cells.

Antigens, Neoplasm↗
PubMed1983

Studies of a high molecular weight human melanoma-associated antigen.

Hybridomas were generated by fusing SP2/0 mouse myeloma cells with spleen cells from mice that had been immunized with cultured human melanoma cells. One of the hybridomas secreted a monoclonal IgG1 antibody, 48.7, which binds to a cell surface antigen of cells from human melanomas and compound nevi. The presence of the target antigen in vivo was demonstrated immunohistologically by staining frozen sections of primary and metastatic melanoma by the peroxidase anti-peroxidase technique. Weak staining of some blood vessel cells was also seen, but other normal cells, including skin melanocytes, were unstained, as were cells from other tumor types. Antibody 48.7 immunoprecipitated polypeptides with apparent m.w. on sodium dodecyl sulfate-polyacrylamide gel electrophoresis of 250,000 and greater than 400,000.

Animals↗
PubMed1983

Imaging of melanoma with L-131-labeled monoclonal antibodies.

Mouse monoclonal antibodies and Fab fragments specific for p97, a melanoma-associated antigen, were used to image metastatic human melanoma. Preclinical studies in athymic mice showed antigen-specific uptake in melanoma xenografts, and toxicity tests in rabbits gave no evidence for tissue damage after injection of up to 100 times the amount of antibody used in humans. Six patients received 1 mg labeled antibody, and one patient received 1 mg of labeled Fab. No. toxic side effects were observed. All of the six patients had positive scans, visualizing 22 of 25 (88%) of lesions larger than 1.5 cm. In tumors from two patients, greater uptake of p97-specific, versus control IgG and Fab, respectively, was documented by biopsy. Antibodies to mouse immunoglobulin appeared in three patients receiving 1 mg or more of radiolabeled mouse antibody.

Adult↗