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Biomedical subjects

S Matzku

Publications and source records attributed to S Matzku.

At least 19 recordsLinked to original sources
PubMed1992

Participation in normal immune responses of a metastasis-inducing splice variant of CD44.

A variant of the glycoprotein CD44 (CD44v) that shares sequences with variants causally involved in metastasis formation is transiently expressed on B and T lymphocytes and macrophages after antigenic stimulation and in the postnatal period. Antibodies to the variant hinder in vivo activation of both B and T cells. The observation that a protein domain that is expressed on CD44 and required for the lymphatic spread of tumor cells can catalyze an essential step in the process of lymphocyte activation supports the idea that metastasizing tumor cells mimic lymphocyte behavior.

Animals↗
PubMed1992

A bifunctional HBED-derivative for labeling of antibodies with 67Ga, 111In and 59Fe. Comparative biodistribution with 111In-DPTA and 131I-labeled antibodies in mice bearing antibody internalizing and non-internalizing tumors.

To investigate whether bifunctional ligands containing chelating structures other than EDTA and DTPA and metallic radiotracers other than 111In will reduce the non-specific radioactivity uptake in the liver during immunoscintigraphy, we synthetized an isothiocyanato-substituted phenolic polyaminocarboxylic acid (HBED-CI) for labeling of MAbs with 67Ga, 111In and 59Fe. Biodistribution of HBED-CI-labeled MAbs was compared to that of 131I and 111In-DTPA labeled MAbs in nude mice bearing tumors, which differ with regard to intracellular internalization and catabolism of the corresponding MAb-antigen complex. In the liver a continuous radioactivity excretion for 67Ga-HBED-CI-labeled MAbs was observed with kinetics that parallel 131I clearance after administration of 131I-MAbs, while 111In-HBED-CI-labeling led to a constant 111In liver level quite similar to that of 111In-DTPA-MAbs. In tumors, 67Ga-HBED-CI-MAb uptake again paralleled that of 131I-MAbs, showing continuous accumulation in tumor tissues when internalization of the MAb-antigen complex was not involved. A much lower uptake, which peaked between 24 and 48 h, was found in the case of MAb-antigen internalization. 111In of 111In-HBED-CI- and 111In-DTPA-labeled MAbs continuously accumulated in both types of tumors. Compared with 111In-DTPA-MAbs, an improvement in tumor-to-liver ratios, due to the reduced liver radioactivity associated with 67Ga-HBED-CI-labeled MAbs, could only be obtained with non-internalizing tumors. The time course of radioactivity distribution in the liver and in MAb-internalizing tumors after administration of 67Ga-HBED-CI-, 111In-HBED-CI- and 111In-DTPA-labeled MAbs further indicates a dominating influence of the metallic radiotracer rather than the ligand on retention or excretion of radioactivity in MAb-catabolizing tissues.

Animals↗
PubMed1992

Establishment and characterization of monoclonal antibodies against an octahedral gallium chelate suitable for immunoscintigraphy with PET.

As a prerequisite for preparing bispecific antibody conjugates containing anti-tumor and anti-metal chelate binding sites that can be used for pretargeted immunoscintigraphy, monoclonal antibodies (Mabs) have been raised against an octahedral metal chelate synthetized from gallium (Ga) and the hexadentate ligand N,N'bis[2-hydroxy 5-(ethylene beta carboxy) benzyl] ethylenediamine N,N' diacetic acid (Ga-HBED-CC). With use of the Farr assay, binding studies with the 67Ga-labeled chelate and three clones of anti-chelate Mabs showed that none of the Mabs were able to precipitate more than 50% of the Ga-chelate, suggesting an enatiomerism of the Ga-chelate and a sensitivity of the Mabs to either one or the other chelate enantiomer. This could be confirmed by comparing the circular dichroism spectra of the Ga-chelate fractions that passed affinity columns containing the Mabs immobilized on sepharose without retention. With use of a Ga-HBED-CC enantiomer, whole-body retention in mice, preinjected with the corresponding anti-metal chelate Mab of ca. 70% ID, was measured compared to 2.1% retention in mice not preinjected with the Mab. Due to the high affinity of chelate-to-Mab binding in vivo, bispecific antibody conjugates prepared from the fragments of the anti-Ga-chelate Mab might be suitable for pretargeted immunoscintigraphy with the short-lived positron-emitter 68Ga.

Animals↗
PubMed1991

Use of combination of monoclonal antibodies directed against three distinct epitopes of a tumor-associated antigen: analysis of cell binding and internalization.

Three monoclonal antibodies (MAbs), MOv17, MOv18 and MOv19 with tumor-restricted specificity for human ovarian carcinoma, were tested alone or in double combination with the aim of analyzing their binding and internalization behavior on different in vitro cell lines. Biochemical studies indicated that the 3 MAbs were directed against 3 epitopes of the same 38 kDa surface molecule. By immuno-electron-microscopy they exhibited a different internalization behavior since MOv17 induced evident endocytosis through coated vesicles, whereas MOv18 gave rise to occasional uncoated vesicles and MOv19 was completely unable to promote internalization of the relevant molecule. When tested 2 by 2 there was a binding synergy in one of the 9 possible combinations (125I-labelled MOv18 and unlabelled MOv19), but no change in the internalization behavior. The binding synergy, which was highly reproducible, was temperature-dependent and was also evident on glutaraldehyde-fixed cells. A metabolism involvement is therefore unlikely. This could be attributed to an easier accessibility of the CaMOv18 due to a conformational change of the molecule after MOv19 MAb binding.

Allosteric Regulation↗
PubMed1991

A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells.

Using a monoclonal antibody (MAb1.1ASML) raised against a surface glycoprotein of the metastasizing rat pancreatic carcinoma cell line BSp73ASML, cDNA clones have been isolated that encode glycoproteins with partial homology to CD44, a presumed adhesion molecule. In one of the clones, pMeta-1, the epitope marks an additional extracellular domain of 162 amino acids inserted into the rat CD44 protein between amino acid positions 223 and 247 (by analogy to human and murine CD44). The new variants are expressed only in the metastasizing cell lines of two rat tumors, the pancreatic carcinoma BSp73 and the mammary adenocarcinoma 13762NF; they are not expressed in the non-metastasizing tumor cell lines nor in most normal rat tissues. Overexpression of pMeta-1 in the nonmetastasizing BSp73AS cells suffices to establish full metastatic behavior.

Amino Acid Sequence↗
PubMed1991

Detachment of cell surface-bound anticarcinoembryonic antigen immune complexes by phospholipase C.

CEA as well as normal cross-reacting antigens (NCA) are fixed to the cell membrane via phosphatidylinositol (PI). To find out whether these antigens are internalized after antibody contact, acid pH desorption was compared to phospholipase C (PLC)-mediated cleavage of the antigen anchor. With the former procedure, marked differences in the desorbability of individual MAbs were noted, while PLC was able to cleave off surface-bound immune complexes irrespective of the MAb involved. From this it is concluded that internalization of MAb complexes of CEA/NCA, if occurring at all, is a low efficiency process.

Antibodies, Monoclonal↗
PubMed1990

Retardation of metastatic tumor growth after immunization with metastasis-specific monoclonal antibodies.

The influence of 4 murine monoclonal antibodies (MAbs) directed against surface determinants of a metastasizing rat adenocarcinoma (BSp73ASML) on metastatic spread was evaluated and compared to their in vivo binding as well as to the induction of a humoral anti-MAb response, especially with respect to the development of anti-idiotypic (ID) antibodies of the internal image type. In a protocol of explicit immunization, all 4 MAbs transiently inhibited metastatic growth. Survival was prolonged only with one MAb (4.4ASML). With another MAb (1.1ASML), directed against a new variant form of CD44, metastatic growth was accelerated after transient retardation. Retardation of metastatic growth correlated with the humoral anti-MAb response. This accounted for the isotype- as well as for the idiotype-specific response. An exception was noted after immunization with MAb 1.1ASML. Rats with high levels of anti-1.1ASML antibodies, which inhibited binding to the tumor cells (internal image-type antibodies) showed accelerated metastatic spread. Data are interpreted to mean that MAb-induced inhibition of metastatic spread may be based on 2 independent mechanisms: blockade of metastasis-associated epitopes (i.e., with MAb 1.1ASML) and induction of an anti-mouse Ig response. In the latter case it was irrelevant whether the response was isotype- or idiotype-specific.

Adenocarcinoma↗
PubMed1990

Tumour targeting with antibody-coupled liposomes: failure to achieve accumulation in xenografts and spontaneous liver metastases.

The potential of small unilamellar liposomes coupled to anti-tumour monoclonal antibodies (immunoliposomes) to accumulate in solid tumour tissue was tested in two systems, i.e. a human malignant melanoma xenografted into nude mice and a syngeneic murine lymphoma ESb.Mp exhibiting spontaneous metastasis to the liver. Both monoclonal antibodies tested were partly released from immunoliposomes within a few hours, thus generating a seemingly constant level of circulating antibody. Nevertheless it was possible to follow the biodistribution of intact immunoliposomes by virtue of a radioiodine label incorporated into the lipid moiety. It was found that in both tumor systems, though they differed with respect to the size of lesions and maybe also to the vascular architecture of surrounding tissue, immunoliposome uptake was virtually nil. The blockade of uptake into solid tumour tissue was caused by the limited availability of immunoliposomes due to their moderate stability, but especially by the inability of the particulate carrier to extravasate.

Animals↗
PubMed1990

Antibody accumulation in small tissue samples: assessment by quantitative autoradiography.

Uptake of radiolabeled 125I monoclonal antibodies in small metastases can only be characterized by autoradiographic techniques. To obtain quantitative data out of autoradiographic images, a transformation of the essentially two-dimensional signal into the Bq per unit volume information is needed. Part of the calibration problem could be solved by using tissue-equivalent standard preparations. However, when aiming at a quantification of radioactivity in small areas (less than or equal to 2 mm diameter), special criteria had to be expanded upon for the reconstruction of the area in the dose matrix and for the correct integration of the radioactivity content.

Animals↗
PubMed1990

Autoradiographic evaluation of monoclonal antibodies' access to melanoma-associated antigens in melanoma xenografts.

Autoradiography of nude mice bearing human malignant melanoma xenografts was performed to characterize the distribution pattern of radioiodinated anti-melanoma monoclonal antibodies (MoAb) and fragments in macroscopic tumor nodules. Non-uniformity of radioactivity distribution was seen in all MoAb-xenograft combinations. The predominant patterns were marked deposition of radioactivity either in the periphery of nodules or in sharply delimited intra-tumoral foci. These patterns were generated by limitations in the accessibility of melanoma tissue rather than gross necrosis or heterogeneity of antigen expression. Computer-aided densitometry of autoradiograms was used to elaborate the difference of accumulation in intra-tumoral hot spots versus cold areas. It was found that increasing uniformity was achieved by increasing the dose of MoAb (i.e., intact IgG) injected, whereas a reduction in the size of MoAb (IgG greater than F(ab')2 greater than Fab) showed no such effect.

Animals↗
PubMed1990

Uptake of indium-111 in the liver of mice following administration of indium-111-DTPA-labeled monoclonal antibodies: influence of labeling parameters, physiologic parameters, and antibody dose.

Liver uptake of indium-111 (111In) in mice was investigated following administration of 111In-DTPA murine monoclonal antibodies (111In-DTPA-MAbs) labeled by the cyclic anhydride method. Biodistribution of HPLC-purified 111In-DTPA-MAb preparations was checked with a low (0.2 micrograms) and a high (8.0 micrograms) MAb dose. Using Bio Gel P-30 for desalting the MAb-conjugates, 111In uptake in the liver amounted to 8%-9% of the injected dose (ID) and was independent from the MAb dose, the DTPA-to-MAb molar ratio, tumor growth and biologic variability (different MAbs and different strains of mice). Using Sephadex G-25 for desalting, 0.2 micrograms doses from 7 out of 26 preparations showed increased liver accumulation of 111In in non-tumor mice ranging from 15%-25% of ID. Corresponding high doses led to a "normal" value of 8%-9%. Increased liver uptake of the low dose could not be reduced by coadministration of the unconjugated MAb, but was normal after reinjection of "in vivo filtered" material. An inverse intracellular distribution of 111In activity between sediment and supernatant of liver homogenates, following the administration of the low and the high MAb dose, indicated an artifact of the labeling procedure rather than an inherent biological property of labeled MAbs.

Animals↗
PubMed1990

Antibody transport and internalization into tumours.

Internalization of monoclonal antibody (MAb) conjugates is an important feature of tumour targeting, both with respect to the therapeutic action of substances coupled to the antibody and to retention of radionuclides. Problems of analysing internalization in vitro and in vivo, of manipulating internalization, and of evaluating the involvement of normal tissues are illustrated by recent experimental data and are discussed in the light of published evidence.

Animals↗
PubMed1990

Accumulation characteristics of human colon carcinomas after monoclonal antibody ex vivo perfusion.

Human colon carcinomas were operatively resected and the tumour-bearing segments interposed into an oxygenised ex vivo perfusion system. Pressure, flow, temperature, pH and metabolic parameters were controlled. Over a period of 45 min the 131I-labelled monoclonal antibody AUA1 was administered and its distribution in the tumour tissue analysed scintigraphically. The accumulated activity was determined in different tissues. The results showed that the AUA1 uptake increased with the degree of histological tumour differentiation. The main tumour:non-tumour ratio reached 0.8 in poorly, 4.1 in moderately and 5.9 in highly differentiated adenocarcinomas. Introducing the oxygenised erythrocyte-enriched perfusion media significantly increased the viability of the colon tissue. The ex vivo perfusion system will help to analyse factors determining monoclonal antibody accumulation in human colon carcinomas.

Adenocarcinoma↗
PubMed1990

Quantitation of antibody uptake in spontaneous metastases.

A procedure of high resolution quantitative autoradiography was established and tested in the murine ESb-Mp lymphoma system. Using 125I-labelled antibody 12-15A, liver metastases with diameters down to 100 microns were identified and intralesional radioiodine accumulation was assessed as % injected dose (iD) g-1. Uptake was found to be highest in intermediate size metastases, i.e., up to 100% iD g-1 in 1 mm lesions, while it gradually declined with both increasing and decreasing diameters of metastases. Lower uptake in large size metastases was due to a marked non-uniformity in radioactivity retention, while lower uptake in small metastases was possibly due to insufficient access of the antibody to intrahepatic processes which have not yet established an autonomous blood supply.

Animals↗
PubMed1989

Monoclonal antibody-mediated tumor regression by induction of apoptosis.

To characterize cell surface molecules involved in control of growth of malignant lymphocytes, monoclonal antibodies were raised against the human B lymphoblast cell line SKW6.4. One monoclonal antibody, anti-APO-1, reacted with a 52-kilodalton antigen (APO-1) on a set of activated human lymphocytes, on malignant human lymphocyte lines, and on some patient-derived leukemic cells. Nanogram quantities of anti-APO-1 completely blocked proliferation of cells bearing APO-1 in vitro in a manner characteristic of a process called programmed cell death or apoptosis. Cell death was preceded by changes in cell morphology and fragmentation of DNA. This process was distinct from antibody- and complement-dependent cell lysis and was mediated by the antibody alone. A single intravenous injection of anti-APO-1 into nu/nu mice carrying a xenotransplant of a human B cell tumor induced regression of this tumor within a few days. Histological thin sections of the regressing tumor showed that anti-APO-1 was able to induce apoptosis in vivo. Thus, induction of apoptosis as a consequence of a signal mediated through cell surface molecules like APO-1 may be a useful therapeutic approach in treatment of malignancy.

Animals↗
PubMed1989

Antigenic differences between metastatic and nonmetastatic BSp73 rat tumor variants characterized by monoclonal antibodies.

Variants AS and ASML of the BSp73 rat tumor differ markedly with respect to morphology and to the capacity for spontaneous metastasis via the lymphatics. Monoclonal antibodies (MAbs) were raised in order to identify surface molecules associated with both phenotypes. Mice were immunized with either whole cells or isolated membranes and hybridoma supernatants were screened according to the criteria of selective binding to cultured cells of the variant used for immunization. Of two MAbs reacting with the nonmetastasizing AS variant, one showed immunostaining of AS tissue. From 11 MAbs binding to the metastatic ASML variant, 6 showed specific staining of ASML tissue, while the remaining 5 MAbs showed cross-reaction with normal rat tissues. According to Western blot data, the 6 MAbs selectively binding to ASML tissue identified at least 2 different antigens, one of them showing up as a complex of 12 bands.

Animals↗
PubMed1989

Melanoma targeting with a cocktail of monoclonal antibodies to distinct determinants of the human HMW-MAA.

The monoclonal antibodies (MoAbs) 149.53, 225.28, and 763.74 which recognize distinct and spatially distant determinants of the human high molecular weight-melanoma associated antigen (HMW-MAA) do not influence the binding of each other to cultured human melanoma cells. In vitro incubation of melanoma cells with a combination of the three 125I-labeled anti-HMW-MAA MoAbs results in a marked additive binding only when the MoAbs are used at saturating concentrations. Injection of the combination of the three 125I-labeled MoAbs (up to 300 micrograms per mouse) into human melanoma-bearing nude mice does not increase the amount of radioactivity specifically localized in melanoma lesions above the level observed upon injection of corresponding doses of individual MoAbs. These results may reflect the low concentration of MoAbs which reaches tumor lesions in vivo. Therefore, administration of combinations of MoAbs to distinct determinants of HMW-MAA may not increase the sensitivity of immunoscintigraphy to visualize lesions in patients with melanoma.

Animals↗