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Biomedical subjects

I Hellström

Publications and source records attributed to I Hellström.

At least 109 records · Page 6Linked to original sources
PubMed1987

Increased delivery of tumor-specific monoclonal antibodies to brain after osmotic blood-brain barrier modification in patients with melanoma metastatic to the central nervous system.

We evaluated the delivery of melanoma-specific radiolabeled monoclonal antibody (MAb) Fab fragments in a pilot study of three patients with melanoma metastatic to the central nervous system. Tumor samples demonstrated excellent immunohistochemical reactivity with Fab 96.5, specific for a 97,000-molecular-weight melanoma antigen (p97), or Fab 48.7, specific for a melanoma-associated proteoglycan antigen. All three patients received 131I-labeled tumor-specific Fab (5 to 7 mg, 1 mCi/mg) intravenously. On a separate occasion, two patients received 131I-labeled nonspecific Fab (5 to 7 mg, 1 mCi/mg). There was no uptake of either antibody into the region of the tumor (as documented by gamma camera brain images). However, there was increased uptake in the blood-brain barrier (BBB)-modified areas in all three patients when radiolabeled tumor-specific MAb was administered intravenously in conjunction with osmotic BBB opening. In one patient, the estimated cerebrovascular permeability X capillary surface area (PA) for the tumor-bearing hemisphere 3 hours after disruption was 1.16 X 10(-6) sec-1 compared to the PA of 0.395 X 10(-6) sec-1 in the nondisrupted hemisphere. Serial brain scans showed that greater than 90% of the radiolabeled antibody cleared from the brain by 72 hours. The highest radiation doses (rads) calculated per 7 mCi injection were: left brain (barrier-modified hemisphere), 5.46; right brain (non-barrier modified hemisphere), 1.68; thyroid, 98; stomach, 9.1; kidney, 39.9; and total body, 1.33. There seemed to be increased uptake of antibody in the tumor region after barrier modification in one patient, but antibody clearance from that region occurred at the same rate as from surrounding and apparently tumor-free brain. In one patient who had carcinomatous meningitis, we demonstrated antibody bound to only a fraction of the antigen binding sites on tumor cells in the cerebrospinal fluid after BBB modification. We have not shown distinct, persistent localization of antibody in brain tumor; studies investigating MAb dose and other parameters as the basis for this problem are under way.

Antibodies, Monoclonal↗
PubMed1986

Identification of a novel serum protein secreted by lung carcinoma cells.

The murine anti-human lung tumor monoclonal antibody L3 recognizes antigens found both in the medium of cultured carcinoma cells and in normal human serum. Sequential immunoprecipitation experiments indicate that the L3 antigen is also recognized by a previously described monoclonal antibody directed against a melanoma-associated antigen [Natali, P. G., Wilson, B. S., Imai, K., Bigotti, A., & Ferrone, S. (1982) Cancer Res. 42, 583-589]. This antibody precipitated a Mr 76000 glycoprotein from metabolically labeled extracts of the lung carcinoma cell line Calu-1 and a Mr 94 000 glycoprotein from labeled culture medium. Pulse-chase experiments suggested a precursor-product relationship between these molecules. Analysis of glycosidase sensitivities of the two forms indicated that maturation of carbohydrate side chains correlated with the apparent increase in molecular weights. L3 antigenic activity, measured in a competitive radiometric cell binding assay, was purified more than 90-fold from serum-free medium of Calu-1 cells and more than 3000-fold from normal human serum. The major immunoreactive components purified from culture medium and serum were identical with respect to apparent molecular weight, electrophoretic mobility, pI, glycosidase sensitivity, and V8 protease fingerprints. In addition, the sequence of the amino-terminal 16 N-terminal amino acid residues of the major immunoreactive species from both sources was identical. The properties of the L3 antigen did not correspond to those of any known protein, suggesting that this serum protein has not been previously characterized.

Amino Acid Sequence↗
PubMed1986

Autoradiolysis of iodinated monoclonal antibody preparations.

We investigated the effects of ionizing radiation on the immunointegrity of antibody fragments (Fab) because large amounts of high specific activity 131I may damage the proteins. We found that 1000 Gy of external 137Cs gamma radiation was sufficient to destroy 80-90% of the immunointegrity of the initial preparation. This effect was also produced by internally added [131I]NaI in a quantity sufficient to provide the same radiation absorbed dose. Since radioiodinated monoclonal antibodies labeled to high specific activity are being evaluated for radioimmunotherapy, the above observation is significant since high levels of internal radiation occur with therapeutic doses of 131I-labeled antibody. Human serum albumin in low concentration (2%) added to the iodinated antibody solutions was successful in preventing loss of immunoreactivity and can be used to protect and stabilize therapeutic quantities of radiolabeled monoclonal antibody preparations.

Antibodies, Monoclonal↗
PubMed1986

Antitumor effects of L6, an IgG2a antibody that reacts with most human carcinomas.

Mouse monoclonal antibody L6 (IgG2a subtype) recognizes a ganglioside antigen expressed at the surface of cells from human non-small-cell lung carcinomas, breast carcinomas, and colon carcinomas. We now show that this antibody can lyse L6 antigen-positive human tumor cells in the presence of Leu-11b-positive human lymphocytes (i.e., mediate antibody-dependent cellular cytotoxicity) or human serum (mediate complement-dependent cytotoxicity) and that it can inhibit the outgrowth of an L6 antigen-positive human tumor transplanted onto nude mice.

Animals↗
PubMed1986

The melanoma proteoglycan: restricted expression on microspikes, a specific microdomain of the cell surface.

A cell surface chondroitin sulfate proteoglycan associated with human melanomas and defined by mAb's F24.47 and 48.7 has been characterized biochemically and localized by indirect immunogold electron microscopy. These antibodies recognize distinct epitopes on the intact proteoglycan. In addition, mAb 48.7 also recognizes an epitope on a 250,000-D glycoprotein and is therefore similar to antibody 9.2.27 (described by Bumol, T.F., and R.A. Reisfeld, 1982, Proc. Natl. Acad. Sci. USA., 79:1245-1249). Furthermore, it was shown that the glycosaminoglycan chains released by alkaline borohydride treatment of the proteoglycan recognized by mAb 48.7 had a size of approximately 60,000 D. Since the intact proteoglycan was estimated to be 420,000 D, there are probably three chondroitin sulfate chains attached to the 250,000-D core glycoprotein. Furthermore, an oligosaccharide fraction containing 42% of the 3H activity (glucosamine as precursor) was isolated. Immunolocalization studies using whole-mount electron microscopy revealed that the chondroitin sulfate proteoglycan was present almost exclusively on microspikes, a microdomain of the melanoma cell surface. These processes were present as 1-2-micron structures on the upper cell surface and as longer (up to 20 micron) structures at the cell periphery. Peripheral microspikes were involved in the initial interactions between adjacent cells and formed complex footpads that made contact with the substratum. Immunogold-labeled cells were also thin sectioned and the specific localization of the chondroitin sulfate proteoglycan antigen was quantitated. The data confirmed the results of whole-mount microscopy and demonstrated a statistically significant association of the antigen with the microspike processes as compared with other areas of the cell surface. By using two different mAb's (48.7 and F24.47) that recognize epitopes on either the core glycoprotein or the intact proteoglycan, respectively, we have demonstrated that both molecules have the same restricted distribution at the cell surface. The specific localization of the antigen to microspikes at the cell surface suggests it may play a role in cell-cell contact and cell-substratum adhesion, which could be important in the metastatic process.

Aggrecans↗
PubMed1986

Monoclonal antibody imaging of human melanoma. Radioimmunodetection by subcutaneous or systemic injection.

Fab fragments of monoclonal antibodies (MoAb) to melanoma, radiolabeled with 131I, were evaluated as diagnostic reagents to determine their ability to localize systemic--MoAb injected intravenously (IV)--or nodal metastatic disease--injected subcutaneously (SQ) at a site proximal to draining lymph nodes. Sixty-one scans were performed (40 IV, 21 SQ) in 59 patients who had injections of 0.2-50 mg of 131I coupled (0.2-12 mCi) antibody. These included 48.7, which identifies a high molecular weight antigen (HMW), or 96.5, which identifies a transferrin like molecule, p97. 125I coupled nonspecific Fab 1.4, reacting with murine leukemia virus, or the whole antibody BL3, reactive with a human B cell idiotypic determinant, was generally used in tandem with the patients injected SQ as a nonspecific control. All patients had immunohistochemical studies performed on biopsied lesions and demonstrated binding to the antibodies injected. Of the IV patients, 22/38 (58%) had (+) scans, 13 at SQ or nodal sites, four at visceral sites, and five at visceral and SQ sites. Patients with clinical stage II disease had SQ injection of MoAb, including 11 additional patients injected with the whole antibody 9.2.27 (anti-HMW) labeled with 111In (6 patients) or 131I (5 patients). Nodal dissection was performed 2-4 days later. All 111In coupled antibodies demonstrated excellent nodal delineation without specific identification of tumor deposits. Of the 21 patients injected SQ with MoAb, 17 had confirmed tumor in nodes. Of patients injected with Fab fragments, 4/8 (50%) had specific uptake of MoAb, although only two were successfully imaged. Increased uptake of antimelanoma antibodies was observed in some patients in lymph nodes not containing tumor and was possibly related to antigen shedding. Clearance of labeled antibody from the injection site occurred with a half life of 16-50 hours. Toxicity was limited to local discomfort at the site of SQ injection. Melanoma metastases can be identified with IV or SQ injection or radiolabeled antibodies. These reagents may be useful in the diagnosis or therapy of human melanoma. Further evaluation will be required before they could be considered clinically useful.

Adult↗
PubMed1986

Immunoreactivity assay for labeled anti-melanoma monoclonal antibodies.

A convenient, rapid, and reproducible assay was developed to evaluate the immunoreactivity of radiolabeled monoclonal antibodies against three different human melanoma-associated antigens, p97, a proteoglycan and a GD3 ganglioside. A cloned melanoma cell line (M 2669 CL 13) was selected as the target and, when fixed with paraformaldehyde, showed binding as good as or better than that obtained with live cells for the three antigens. Fixed cells retained good binding properties stored at 4 degrees C for over 6 mo. This assay has general applicability to other antigen-antibody systems for testing chemically modified monoclonal antibodies or fragments during the development of a radiopharmaceutical or as a routine quality control measure for clinical agents.

Antibodies, Monoclonal↗
PubMed1986

Monoclonal mouse antibodies raised against human lung carcinoma.

We have evaluated approximately 10,000 monoclonal antibodies (MoAb) resulting from 25 hybridizations of spleen cells from mice immunized with cells from human non-small cell lung carcinoma or fetal lung. The spleen cells were hybridized with NS-1 myeloma cells, and the resulting hybridomas were screened for production of MoAb to non-small cell lung carcinoma by binding assays with either cell extracts or cells growing in culture, followed by immunohistology on frozen sections. Fourteen MoAb had relative specificity for non-small cell lung carcinoma versus normal tissues. Three of these MoAb (L3, L6, L17) also reacted with most carcinomas of the breast and colon, and two MoAb (L20 and L22) reacted with the four samples of small cell lung carcinoma tested. No MoAb defined an antigen of absolute tumor specificity, and no MoAb reacted substantially more with adenocarcinoma than squamous cell carcinoma of the lung (or vice versa). Five MoAb were Ig G1, two were Ig G2a, and the remaining seven were Ig M. Seven MoAb (L5, L6, L15, L17, L20, L22, L23) could bind to the cell surface. Three MoAb (L6, L15, L17) defined carbohydrate antigens, and three (L3, L5, L20) were to protein antigens, while the antigens to which the remaining MoAb are directed have not been identified. Six MoAb could bind to tumor cells in Carnoy-fixed paraffin-embedded sections. An intercellular variability in antigen expression was detected with all 14 MoAb. At least two of the MoAb, L6 and L20, are good candidates for preclinical testing in view of their high level of tumor selectivity, as shown by both immunohistology and binding assays with living cells.

Animals↗
PubMed1985

Mouse monoclonal antibodies with specificity for the melanoma-associated ganglioside disialyllactosylceramide (GD3) also react with the structural analogue disialylparagloboside.

A mouse monoclonal IgM antibody, 4.2, has previously been shown to bind preferentially to the surface of human malignant melanoma cells and to have specificity for the GD3 ganglioside (NeuAc alpha 2----8NeuAc alpha 2----3Gal beta 1----4GlcCer). Using overlay of antibodies on thin-layer chromatograms with glycolipids of various sources, it was shown that antibody 4.2, a further IgM and two IgG3 mouse monoclonal antibodies, selected on the basis of reactivity with GD3, also bound with similar strength to the structural analogue NeuAc alpha 2----8NeuAc alpha 2----3Gal beta 1----4GlcNac beta 1----3Gal beta 1----4GlcCer or disialylparagloboside. The SK-MEL 28 melanoma cell line used for immunization was shown to contain a large amount of GD3 but to lack disialylparagloboside. The demonstrated cross-reactivity may be of importance when considering the use of these antibodies for biochemical and medical purposes.

Animals↗
PubMed1985

Antitumor properties of vindesine-monoclonal antibody conjugates.

The anticancer alkaloid vindesine (VDS) was conjugated to four mouse monoclonal antibodies recognizing human tumor-associated antigens. The antibodies were 96.5 (antimelanoma, IgG2a); 791T/36 (antiosteogenic sarcoma, IgG2b); 11.285.14, and 14.95.55 (anticarcinoembryonic antigen, IgG1 and IgG2a respectively). Conjugates VDS-96.5 and VDS-791T/36 were tested in vitro and shown to be specifically cytotoxic for target cells expressing the appropriate antigen. The in vivo effects of the antibodies and conjugates were tested against human tumor xenografts in athymic or immunodeprived mice using multiple treatments. Conjugate VDS-96.5 retarded the initial growth of a melanoma xenograft, whereas free antibody was without effect. Similarly, VDS-791T/36 but not free antibody retarded the growth of osteogenic sarcoma 791T. The most marked antitumor effects observed were those obtained with VDS conjugates of the anti-CEA antibodies against a colorectal tumor xenograft. Antibody 14.95.55 suppressed tumor growth both alone and as a VDS conjugate, whereas 11.285.14 produced only a slight effect alone but an almost complete and lasting suppression of tumor growth as a VDS conjugate. Free VDS had little effect at nontoxic levels. Acute studies showed that VDS-11.285.14 conjugate was considerably less toxic than free VDS in Balb/c mice.

Animals↗
PubMed1985

A monoclonal antibody recognizing cytoskeletal keratins of stratified epithelia and bladder carcinomas.

Monoclonal antibodies were generated by immunizing rats with mouse bladder carcinomas, fusing their spleen cells with NS-1 myeloma cells and selecting for antibodies that bound to mouse bladder carcinomas. One of the antibodies, IG5, recognizes an antigenic determinant which is present in mouse bladder carcinoma cytoskeletons and is not detectable in the normal bladder epithelium. Indirect immunofluorescence studies revealed that the antigen is expressed intracellularly and is organized in the form of filamentous arrays. The antigen was detected by peroxidase--antiperoxidase immunocytochemistry in stratified epithelia and glands derived from these, but has not been observed in any tissues of mesenchymal or neuronal origin. Various normal and neoplastic human tissues were subsequently tested for reactivity with antibody IG5. Antigen expression in normal tissues was similar to that in the mouse. Most carcinomas of the bladder and lung were stained, while all of eleven colon carcinomas were negative. Antibody IG5 immunoprecipitated radio-iodinated peptides of 58, 56, 52 and 43 kD molecular weight from mouse bladder carcinomas. Western blotting experiments with antibody IG5 demonstrated bands of 56 and 50 kD in a keratin-enriched fraction of the bladder carcinoma cytoskeleton. Antibody IG5 reacted with molecules which have several properties typical of cytoskeletal keratin peptides. Our findings are discussed in the context of previously described keratin peptides and relevant monoclonal antibodies.

Animals↗
PubMed1985

Monoclonal antiidiotypic antibodies related to a murine oncofetal bladder tumor antigen induce specific cell-mediated tumor immunity.

Rat monoclonal antibody 6.10 recognizes a 175-kDa protein expressed in all BALB/c mouse transitional cell bladder carcinomas tested, in epithelial cells of the mouse embryo, and in a few epithelial cells of adult mice. The antibody was used as an immunogen to generate two mouse monoclonal antibodies, 21D9 and 43A10, which bind to idiotopes on antibody 6.10 associated with the binding site for the 175-kDa antigen. The antiidiotypic antibodies induced bladder tumor-specific, cell-mediated immunity when injected into syngeneic mice, as shown by delayed-type hypersensitivity reactions in vivo and leukocyte adherence inhibition reactions in vitro. Tumor specificity was demonstrated by employing as controls a chemically induced BALB/c fibrosarcoma, MCA-1511 (MCA, 3-methylcholanthrene), and its corresponding antiidiotypic antibody, 5.96. Lymphocytes from mice sensitized with antibody 21D9 or 5.96 specifically recognized antigens in extracts of BALB/c bladder carcinoma BTCC-1660 (BTCC, bladder transitional cell carcinoma) and sarcoma MCA-1511, respectively, as shown by leukocyte adherence inhibition reactivity. This reactivity was selectively abrogated by prior treatment of the sensitized cells with the appropriate antiidiotypic antibodies and complement. An antigen recognized in vitro by antibody 21D9-sensitized lymphocytes could be separated from BTCC-1660 extract by immunoabsorption with antibody 6.10 and elution with acidic buffer. Our findings indicate that the oncofetal antigen defined by antibody 6.10 is recognized by the immune system of syngeneic mice and suggest that antiidiotypic antibodies related to certain oncofetal antigens can be used to immunize against syngeneic tumors.

Animals↗
PubMed1985

Strong antitumor activities of IgG3 antibodies to a human melanoma-associated ganglioside.

Three mouse monoclonal IgG3 antibodies, 2B2, IF4, and MG-21, recognize a GD3 ganglioside antigen that is expressed at the cell surface of most human melanomas. All three antibodies mediate antibody-dependent cellular cytotoxicity (ADCC) in vitro when tested with human lymphocytes as effector cells in a 2-hr or 4-hr 51Cr-release test, and one antibody, MG-21, also gives strong complement-dependent cytotoxicity with human serum. Antibody 2B2, which gives ADCC also in the presence of mouse lymphocytes, inhibited the outgrowth of a human melanoma in nude mice, but antibody IF4, which showed no ADCC with mouse lymphocyte effectors, did not.

Animals↗
PubMed1985

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↗
PubMed1985

Long-term recovery of superficial and deep glomeruli after acute renal failure evoked by warm ischemia.

A study was made on the number of glomeruli in the outer cortex, midcortex, and inner cortex 4 weeks after 45 min of warm ischemia, using alcian blue to stain functioning glomeruli. During this time the stainable glomeruli in the kidney as a whole had decreased in number from 32,000 to 16,800. The superficial glomeruli were reduced by only about 30%, whereas in the juxtamedullary zones the number of functioning nephrons were reduced by 80%. This shows that the juxtamedullary nephrons are the most susceptible to degeneration in the recovery phase of acute renal failure caused by ischemia. The decrease in the number of glomeruli was accompanied by a reduction in total glomerular filtration rate to about the same extent. In contrast, the kidney weight was reduced by only about 20%, suggesting compensatory hypertrophy of the remaining tubules. Fluid reabsorption, urine osmolality, and potassium-secreting ability also remained decreased. The contralateral kidney responded with a compensatory hypertrophy and an increase in glomerular filtration rate, whereas the number of glomeruli in the cortex as a whole and in the individual cortical zones in this kidney remained the same as in control kidneys. It is suggested that the trapping of red cells in the juxtamedullary circulation seen soon after restoration of circulation to kidneys subjected to warm ischemia will also cause a further degeneration of the juxtamedullary nephrons.

Acute Kidney Injury↗