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E Boven

Publications and source records attributed to E Boven.

At least 91 records · Page 5Linked to original sources
PubMed1992

Determination of the immunoreactive fraction of radiolabeled monoclonal antibodies directed against intracellular antigens.

For investigations involving monoclonal antibodies (mAbs) against cellular antigens cell binding assays are routinely used to determine the immunoreactive fraction after radiolabeling. In general, surface antigens are targets for radioimmunodetection, but recent studies indicate that intracellular determinants may also prove useful for this purpose. Thus, there is a need to adapt the regular cell binding assay for use with antibodies directed against cytoplasmic antigens. Here we describe a fixation method which permits such mAbs to bind to cell surfaces as well as to intracellular determinants. Moreover, the procedure may be used for antigens that are sensitive to the commonly used aldehyde fixatives. The method is illustrated with two human IgM mAbs 16.88 and 28A32, which recognize cytoplasmic antigens. Human colon cancer cells in suspension were fixed with either acetone or glutaraldehyde. Intracellular antigens appeared to be best exposed for antibody binding after fixation with acetone as determined by immunofluorescent staining and flow cytometry. An antibody directed against the cell surface antigen HLA class I showed similar binding with both live cells and acetone-fixed cells. Double-inverse plots of the binding of radiolabeled 16.88 or 28A32 antibody with acetone-fixed cells gave reliable immunoreactive fraction values. Acetone-fixed cells stored at 4 degrees C could be used for immunoreactivity assays for at least 6 months without loss of performance.

Acetone↗
PubMed1992

Comparison of 131I-labelled anti-episialin 139H2 with cisplatin, cyclophosphamide or external-beam radiation for anti-tumor efficacy in human ovarian cancer xenografts.

Three human ovarian cancer xenografts of different origin and grown s.c. in nude mice as well-established tumors were studied for their sensitivity to cisplatin (CDDP), cyclophosphamide (CTX), 131I-labelled anti-episialin monoclonal antibody (MAb) 139H2, or external-beam radiotherapy. The maximum tolerated dose of CDDP given weekly i.v. x 2 induced a tumor growth inhibition (GI) of 77.5% and 85.1% of the serous xenografts Ov.Ri(C) and OVCAR-3, respectively. The mucinous xenograft Ov.Pe was relatively resistant to CDDP. The maximum tolerated dose of CTX, given i.p. x 2 with a 2-week interval, induced a GI between 52.9% and 59.7% for each of the 3 xenografts. Radioimmunotherapy with 500-750 microCi 131I-specific MAb 139H2, administered i.v. x 2 with a 2-week interval, was more effective than CDDP or CTX. The 500 microCi 131I-MAb 139H2 schedule induced 100% GI in Ov.Ri(C) xenografts and all tumors were cured. The same schedule was slightly less effective in OVCAR-3 xenografts, but complete tumor regressions could still be obtained. Ov.Pe xenografts were least sensitive to radioimmunotherapy. The 2 injections of 500 microCi 131I-control MAb gave only transient growth inhibition of OVCAR-3 and Ov.Pe tumors, but gave complete regressions of Ov.Ri(C) xenografts. Biodistribution using tracer doses of 131I-MAb 139H2 and 125I-control MAb showed different degrees of specificity for MAb 139H2 in the 3 xenografts. Radiation doses absorbed in OV.Ri(C), OVCAR-3 and Ov.Pe xenografts per 10 microCi injected dose were 30, 41 and 29 cGy respectively. Treatment with 10 Gy external-beam radiation suggested that the effects of radioimmunotherapy in each tumor line were related to the intrinsic radiosensitivity of the xenografts.

Animals↗
PubMed1992

Time dependence of the selective modulation of cisplatin-induced nephrotoxicity by WR2721 in the mouse.

2-(3-Aminopropylamino)ethylphosphorothioic acid (WR2721; ethiofos) was shown to selectively protect nontumor tissues from cis-diamminedichloroplatinum(II) (cisplatin)-induced toxicity, when administered 30 min prior to the platinum drug. Selectivity of protection by WR2721 is probably due to the preferential formation and uptake of the thiol metabolite 2-(3-aminopropylamino)ethanethiol (WR1065), which can inactivate toxic platinum-species inside the cell. We investigated the protective potential of WR2721, when administered at different time points relative to cisplatin. BALB/c mice treated with WR2721 (200 mg/kg i.p.) either 30 min or 5 min prior to cisplatin (i.p.) allowed a 2.2-fold increase in cisplatin dose to 19 mg/kg before the occurrence of nephrotoxicity as expressed by an increase in plasma urea. A small part of the protection could be ascribed to the mannitol (200 mg/kg), present in the formulated WR2721. WR2721 (200 mg/kg) 30 min after 14.5-16-mg/kg cisplatin did not offer any protection against the rise in plasma urea. WR2721 (200 mg/kg) 5 min before 19-mg/kg cisplatin did not cause liver toxicity (increase in serum glutamic pyruvic transaminase or serum glutamic oxaloacetic transaminase). Furthermore, WR2721 (200 mg/kg) 5 min prior to cisplatin did not reduce antitumor activity in nude mice bearing well-established human ovarian cancer xenografts. Under protection of WR2721, the dose of cisplatin could be increased by a factor of 1.6 to 8 mg/kg (administered twice weekly), resulting in an increased antitumor activity.

Amifostine↗
PubMed1992

Influence of dose and schedule on the therapeutic efficacy of 131I-labelled monoclonal antibody 139H2 in a human ovarian cancer xenograft model.

The therapeutic efficacy of various doses and schedules of 131I-labelled anti-episialin monoclonal antibody (MAb) 139H2 was assessed in the NIH:OVCAR-3 human ovarian cancer xenograft model. Radioimmunotherapy was started at the time s.c. tumors were well established (100 to 300 mm3). The anti-tumor effects induced by i.v. injections of 131I-MAb 139H2 were dose- and schedule-dependent. Optimal growth inhibition and long-lasting complete tumor regressions were obtained with 2 injections of 500, 700 or 750 muCi 131I-MAb 139H2 per mouse given with a 2-week interval. The percentage of tumors with more than 50% reduction of their initial volume after treatment with a total dose of 1,000 muCi 131I-MAb 139H2 per mouse, given as 10 injections of 100 muCi (3 x/week), 4 injections of 250 muCi (2 x/week), 10 injections of 100 muCi (5 x/week) within a period of 3 weeks, or 2 injections of 500 muCi with a 2-week interval, was 9%, 40%, 64% and 75% respectively. Unlabelled MAb 139H2 did not affect tumor growth, while the effects of 131I-control MAb were minor and transient. 131I-MAb 139H2 treatment did not select for outgrowth of episialin-negative cells in the OVCAR-3 xenografts. Highest absorbed doses of whole-body-radiation were calculated for 2 injections (500 to 750 muCi 131I-MAb 139H2) given with the 2-week interval. The radiation dose to the tumor after a single injection of 500 muCi 131I-MAb 139H2 was 1,300 cGy over 7 days, which appeared slightly lower than the dose calculated after administration of a tracer dose of iodinated MAb 139H2.

Animals↗
PubMed1992

Analysis of a conjugate between anti-carcinoembryonic antigen monoclonal antibody and alkaline phosphatase for specific activation of the prodrug etoposide phosphate.

The selective targeting of tumors by enzymes conjugated to monoclonal antibodies (mAb) may be an ideal approach to convert relatively nontoxic prodrugs into active agents at the tumour site. We used the anti-carcinoembryonic antigen mAb BW431/26 conjugated to alkaline phosphatase (AP) and phosphorylated etoposide (etoposide-P) as a prodrug to study the feasibility of this concept. Etoposide was phosphorylated with POCl3. Quantitative hydrolysis of etoposide-P to etoposide occurred within 10 min in the presence of AP. BW431/26 and AP were conjugated using a thioether bond. The AP conjugate retained 93% of its calculated activity. 125I-labelled AP conjugate did not show a reduction of immunoreactivity as determined by a cell-binding assay. SW1398 colon cancer cells were used to analyse the cytotoxicity of etoposide and etoposide-P. Etoposide (IC50 22 microM) was 100 times more toxic than etoposide-P (20% growth inhibition at 200 microM). Pretreatment of the cells with BW431/26-AP prior to etoposide-P exposure resulted in a dramatic increase in cytotoxicity (IC50 70 microM). The pharmacokinetics and tumour-localizing properties of BW431/27 and the AP conjugate were assessed in nude mice bearing SW1398 tumours. BW431/26 showed excellent tumour localization (10% of the injected dose/g tissue retained from 8 h to 120 h), whereas the AP conjugate showed a reduced tumour uptake (3%-0.3% of the injected dose/g tissue at 8-120 h), a faster clearance from the circulation and a high liver uptake. Radiolabelled AP showed a similar pharmacokinetic profile to the AP conjugate. Gel filtration analysis of blood, liver, and tumour samples indicated good stability of the conjugate.

Alkaline Phosphatase↗
PubMed1992

Malignant Leydig cell tumor of the testis in complete remission on o,p'-dichlorodiphenyl-dichloroethane.

A 56-year-old patient is described who presented with retroperitoneal lymph node metastases 2 years after resection of a Leydig cell tumor of the left testis. The patient did not suffer from endocrinological imbalance. Surgical removal of the metastases alleviated abdominal symptoms for 1 year. o,p'-Dichlorodiphenyl-dichloroethane (o,p'-DDD) treatment was started at the time of recurrence of the retroperitoneal mass and the appearance of a hepatic metastasis. Tumors were remarkably responsive to o,p'-DDD, since 2 complete remissions could be obtained for extended periods. The o,p'-DDD was tolerated reasonably well and serum levels of 15 to 20 mg./l. were sustained for many months. Unfortunately, the patient could not be cured with this effective treatment.

Humans↗
PubMed1992

Comparison of the pharmacokinetics, biodistribution and dosimetry of monoclonal antibodies OC125, OV-TL 3, and 139H2 as IgG and F(ab')2 fragments in experimental ovarian cancer.

Monoclonal antibody (MAb) 139H2 was previously shown to localise specifically into ovarian cancer xenografts in nude mice. MAb 139H2 was compared with MAbs OC125 and OV-TL 3, all reactive with ovarian carcinomas, for the binding characteristics as IgG and F(ab')2 fragments with the use of the OVCAR-3 cell line grown in vitro and as s.c. xenografts. Immunoperoxidase staining of OVCAR-3 tissue sections with MAbs OC125 and 139H2 was heterogeneous, whereas MAb OV-TL 3 showed homogeneity. No differences in binding were observed between IgG and F(ab')2. The avidity expressed as apparent affinity constants of MAbs OC125, OV-TL 3 and 139H2 for OVAR-3 cells were 1 x 10(9) M-1, 1 x 10(9) M-1, and 1 x 10(8) M-1, while the number of antigenic determinants were 5 x 10(6), 1 x 10(6) and 7 x 10(6), respectively. In OVCAR-3 bearing nude mice the blood half-lives of the MAbs as IgG and F(ab')2 were approximately 50 h and 6 h, respectively. Maximum tumour uptake for the whole MAbs OC125, OV-TL 3, 139H2 and a control MAb 2C7 was 8.5%, 17.7%, 11.1% and 2.5% of the injected dose g-1, reached at 72 h after injection. For the respective F(ab')2 fragments, the maximum values were 5.2%, 10.0%, 5.5% and 1.9% of the injected dose g-1, reached between 6 h and 15 h. Tumour to non-tumour ratios were more favourable for the F(ab')2 fragments as compared to those for MAbs as IgG. Biodistribution in mice bearing a control tumour confirmed the specificity of tumour localisation of MAbs OC125, OV-TL 3 and 139H2. After injection of a tracer dose of 10 microCi of radiolabelled MAbs OC125, OV-TL 3 and 139H2 as IgG, tumours received 38 cGy, and 9 cGy. In our OVCAR-3 model, a ranking in efficiency in tumour localisation would indicate MAb OV-TL 3 as most favourable MAb, but cross-reactivity with subpopulations of human white blood cells might hamper its clinical use. Dosimetric data indicate a 4-fold higher radiation absorbed dose to tumours for IgG compared with F(ab')2 fragments.

Animals↗
PubMed1992

A monoclonal antibody-beta-glucuronidase conjugate as activator of the prodrug epirubicin-glucuronide for specific treatment of cancer.

The anti-pan carcinoma monoclonal antibody (MAb) 323/A3, linked to E. coli-derived beta-glucuronidase (GUS) was used to study the tumour-site-selective activation of the prodrug Epirubicin-glucuronide (Epi-glu). Epi-glu was isolated from the urine of patients treated with Epirubicin (Epi) by reversed phase chromatography on a silica-C18 column. Epi-glu was stable in human blood and was not converted into Epi by A2780, MCF-7, or OVCAR-3 cancer cells, despite the presence of intracellular GUS. The stability of the prodrug was confirmed in BALB/c mice. MAb 323/A3 and GUS were linked through a stable thioether bond. The conjugate (1:1) was purified by ion exchange and gel filtration chromatography. Binding to target cells revealed an immunoreactivity of at least 60% and good retention of enzyme activity. A protein dye (sulforhodamine B) assay was used to analyse cytotoxicity. Epi (IC50 of 0.003-0.2 microM) was 100-1,000 times more toxic than Epi-glu (IC50 of greater than 20 microM), when cancer cells were exposed for 4 or 24 h to the drugs. The low cytotoxicity of Epi-glu was most likely due to the reduced cellular uptake rate of the prodrug (2.7 pmol 10(-6) cells min-1) as compared to that of the parent compound (25 pmol 10(-6) cells min-1). Pretreatment of antigen-positive cells with the 323/A3-GUS conjugate prior to prodrug exposure completely restored cytotoxicity as a result from hydrolysis of Epi-glu into Epi. Our results demonstrate that the 323/A3-GUS conjugate can specifically activate the stable non-toxic prodrug Epi-glu at the tumour cell level.

Antibodies, Monoclonal↗
PubMed1992

The anti-tumour effects of the prodrugs N-l-leucyl-doxorubicin and vinblastine-isoleucinate in human ovarian cancer xenografts.

N-l-leucyl-doxorubicin and vinblastine-isoleucinate can be considered as relatively non-toxic prodrugs from doxorubicin and vinblastine, respectively. A comparative analysis was carried out of the anti-tumour activity of the four compounds as well as vintriptol in four human ovarian cancer xenografts different in histology, growth rate and chemosensitivity. Injections were given i.v. weekly twice into mice bearing well-established s.c. tumours. At equitoxic doses, the amount of drug administered for N-l-leucyl-doxorubicin and vinblastine-isoleucinate was respectively 3-fold and 2-fold higher than the doses of the parent compound. N-l-leucyl-doxorubicin induced a growth inhibition > 50% in three out of four human ovarian cancer lines. The anti-tumour effects obtained were significantly better (P < 0.01) than in the case of doxorubicin. Vinblastine-isoleucinate studied in two of these lines could induce a growth inhibition of > 50%. This prodrug appeared slightly less effective than vinblastine. Insignificant growth inhibition (< 50%) was obtained by vintriptol.

Animals↗
PubMed1992

Experimental and clinical analysis of the characteristics of a chimeric monoclonal antibody, MOv18, reactive with an ovarian cancer-associated antigen.

Monoclonal antibody (Mab) MOv18 preferentially reacts with gynecological carcinomas. We have analyzed the characteristics of murine MOv18 (m-MOv18) and chimeric MOv18 (c-MOv18). We found no differences in affinity and binding to IGROV1 cells between c-MOv18 as IgG and F(ab')2 fragments and m-MOv18. In nude mice bearing IGROV1 xenografts, maximum tumor uptake 6-15 hr after i.v. injection of radiolabeled m-MOv18 IgG, c-MOv18 IgG, c-MOv18 F(ab')2 and a control IgG, 2C7, was 10%, 11%, 3% and 4.5% of the injected dose/g (%ID/g), respectively. M- and c-MOv18 IgG retained this level for several days, while c-MOv18 F(ab')2 and 2C7 cleared rapidly from the tumor. Uptake in normal tissues was low, with the exception of high uptake in kidneys for c-MOv18 F(ab')2. Tumor/blood ratios for c-MOv18 F(ab')2 were sixfold higher than for IgG. Radiation absorbed doses to tumor tissue delivered by 10 microCi iodinated m-MOv18 IgG, c-MOv18 IgG and c-MOv18 F(ab')2 were 39 cGy, 49 cGy and 5 cGy, respectively. A cocktail of 125I-c-MOv18 IgG and 131I-c-MOv18 F(ab')2 injected i.v. into an ovarian cancer patient, localized specifically in the tumor. Ovarian cancer tissue samples obtained 2 days postinjection showed a mean uptake of 1.2 x 10(-3) and 2.7 x 10(-3) %ID/g for c-MOv18 IgG and c-MOv18 F(ab')2, respectively. Results from these in vitro and in vivo experiments indicate that c-MOv18 has promise as a Mab for clinical use.

Adult↗
PubMed1991

Human IgM monoclonal antibody 16.88: pharmacokinetics and immunogenicity in colorectal cancer patients.

Twenty colorectal cancer patients were given an intravenous injection of human IgM monoclonal antibody (MAb) 16.88 (8 mg) conjugated to 131I for tumor localization. After a 2-week interval, a second injection with 200, 500, or 1000 mg of unlabeled antibody added was given to groups of five patients each. at the end of the 2-hour infusion, 66% of the radioactivity remained in the circulation. Blood clearance of the 131I-labeled MAb 16.88 was biphasic with a mean half-life (T1/2 alpha) of 12 hours and T1/2 beta of 45 hours. Clearance rate was 0.09 L/hour. More than 90% of the 131I in serum was protein bound, with an immunoreactive fraction of 80% in the first 48 hours. Size exclusion chromatography indicated no degradation products other than 131I in serum and urine. The urinary excretion rate of 131I increased to 1.5% of the dose per hour at 24 hours, with 50% of the dose excreted in 34 hours. The pharmacokinetic profile of 131I-labeled MAb 16.88 was neither influenced by the total protein dose of antibody administered nor affected by specific uptake in tumor tissue in individual patients, as determined on early immunoscintigrams. The larger antibody doses showed a slightly slower excretion of 131I. The assays applied to determine immunogenicity were enzyme-linked immunosorbent assay, radioimmunoassay, and the dot-blot assay. They had sensitivities ranging from 5 ng/mL to 0.5 micrograms/mL for goat or rabbit antihuman IgM. The assays did not reveal antihuman antibody responses.

Adult↗
PubMed1991

Effects of recombinant human granulocyte-macrophage colony-stimulating factor on myelosuppression induced by multiple cycles of high-dose chemotherapy in patients with advanced breast cancer.

In this study, 18 patients with advanced breast cancer were treated with multiple cycles of doxorubicin (75 or 90 mg/m2) plus cyclophosphamide (750 or 1000 mg/m2) every 21 days. Granulocyte-macrophage colony-stimulating factor (GM-CSF) (250 micrograms/m2 per day) was administered by continuous infusion during 10 days (days 2-12), starting in the first or second cycle of chemotherapy. Sixteen (89%) of 18 patients (95% confidence interval, 65%-99%) achieved an objective remission, five (28%) of which were complete. The median duration of response was 7 months. When GM-CSF was used for the first time, it had an effect on the kinetics of all blood cells, including neutrophils, lymphocytes, thrombocytes, and reticulocytes. However, in subsequent cycles of chemotherapy, the stimulatory effect of GM-CSF on hematopoiesis was substantially diminished. World Health Organization grade 3 and 4 neutropenia and thrombocytopenia necessitated dose reductions of doxorubicin and cyclophosphamide from cycle 2 onward in all patients treated with the highest dose. Side effects of GM-CSF included fever, general weakness, and hypotension. These toxic effects mimicked sepsis, and hospital admission for treatment with intravenous antibiotics was required for 73 days in 61 cycles of chemotherapy that included GM-CSF. Dose-intensive chemotherapy produced a high response rate in patients with advanced breast cancer. However, GM-CSF administered from day 2 to day 12 at a dose of 250 micrograms/m2.

Adolescent↗
PubMed1991

The effects of gamma-interferon combined with 5-fluorouracil or 5-fluoro-2'-deoxyuridine on proliferation and antigen expression in a panel of human colorectal cancer cell lines.

Gamma-Interferon (IFN-gamma) and the antimetabolites 5-fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FUdR) were investigated as individual agents and in combination for their in vitro antiproliferative capacity and for their effect on the expression of HLA class-I antigen, carcinoembryonic antigen (CEA) and the intracellular tumor-associated antigen CTA-I in 7 human colorectal cancer cell lines: WiDr, HT29, Colo 205, SW116, LS174T, SW1398, and LoVo. Growth inhibition by IFN-gamma at clinically relevant concentrations (50-100 U/ml) was found in 4/7 cell lines. The cell lines were equally sensitive to 5-FU (IC50 in a range of 2-10 microM), while sensitivity to FUdR varied considerably (IC50 in a range of 0.01-90 microM). When 50 U/ml IFN-gamma were combined with 5-FU or FUdR, the antiproliferative effects were synergistic in those cell lines with sensitivity to IFN-gamma as a single agent, but not in the IFN-gamma-insensitive cell lines. IFN-gamma was able to enhance the expression of HLA Class I and CEA in 4/7 and 3/7 cell lines, respectively, as measured by flow cytometry. CTA-I expression could not be enhanced with IFN-gamma. The expression of the 3 antigens tested was also increased by 5-FU and FUdR. This effect was concentration-dependent in most instances and varied between the individual cell lines. The combination of 50 U/ml IFN-gamma with 25% growth-inhibitory concentration of 5-FU or FUdR for each cell line resulted in an additional increase in antigen expression in 4/7 cell lines. No relation was found between the enhancement of antigen expression and the sensitivity to IFN-gamma or the anti-metabolites. The enhancement in antigen expression also did not show a relationship with changes in cell-cycle distribution upon exposure to IFN-gamma or the anti-metabolites. These results suggest independent mechanisms for the antiproliferative and antigen-enhancing effects of IFN-gamma, 5-FU and FUdR.

Antibodies, Monoclonal↗
PubMed1991

[The hematopoietic growth factor GM-CSF in chemotherapy for advanced breast carcinoma].

A non-randomized study was carried out in the Free University Hospital, Amsterdam, to investigate the (hematologic) toxicity and antitumor response of patients with advanced breast cancer treated with intensive chemotherapy in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF). Of 11 patients with an inoperable or metastasized breast cancer, 5 were treated with doxorubicin 75 mg/m2 + cyclophosphamide 750 mg/m2 intravenously every 3 weeks and 6 patients with 90 and 1000 mg/m2 respectively. When in a preceding cycle a significant hematologic toxicity was observed, this patient was treated in the subsequent cycle with the same dose of chemotherapy in combination with GM-CSF 250 micrograms/m2/day from day 2-12 as a continuous infusion. Bone marrow depression was diminished in the presence of GM-CSF. This was apparent from a milder decline of the number of neutrophilic granulocytes, reduction of the neutropenic period and a more rapid recovery of the neutrophil number. A transient eosinophilia and a mild monocytosis were also observed. GM-CSF did not improve erythrocyte and thrombocyte counts. The efficacy of GM-CSF was less pronounced in the group of patients with the highest dose of chemotherapy. GM-CSF was associated with malaise, fever and a small decrease of blood pressure, which in combination with a frequently occurring anemia and the side-effects of high dose chemotherapy, resulted in a substantial toxicity. In 9/11 patients an objective tumor regression was noted. GM-CSF stimulated the recovery of granulocytes after intensive chemotherapy. Treatment of a small group of patients with advanced breast cancer with intensive chemotherapy resulted in a high antitumor response.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Human ovarian cancer xenografts in nude mice: characterization and analysis of antigen expression.

We have characterized 13 different human ovarian cancer xenografts grown subcutaneously in nude mice. The tumor lines represented 5 histological subtypes: serous (4), mucinous (4), clear-cell carcinoma (1), carcinosarcoma (1) and undifferentiated (3). The specific histology and the degree of differentiation resembled those of the original patients' tumors and were maintained upon serial transfer. Volume doubling times of the xenografts ranged from 3.5 to 15 days. The xenografts were also analyzed for their antigen expression using 20 monoclonal antibodies (MAbs) reactive with 15 tumor-associated antigens. Immunohistochemical examination of tissue sections showed a positive reaction pattern with MAbs 115D8, 140C1, 139H2, 175C5, HMFG1 and HMFG2, each recognizing episialin, as well as with MAbs AUA1, 358.4.32 and 199-157 in xenografts of the serous, mucinous and clear-cell carcinoma subtype. MAb OC125 was reactive with xenografts of the serous subtypes. Other antibodies, such as 494 and OV-TL3 infrequently demonstrated positive reactions. Reactivity of all MAbs was low in the carcinosarcoma and undifferentiated tumor lines. With the exception of AUA1, 495 and 126E5, all MAbs revealed a heterogeneous staining pattern. MAbs against episialin and OC125 predominantly stained the apical site of the tumor cells. Strongest reactivity with almost all histological subtypes was observed with MAbs 115D8, 140C1, 139H2 and AUA1. In cases where we were able to compare the patients' tumor tissue with the respective xenografts, retention of antigen expression was demonstrated in each instance. Release of tumor-associated antigens was shown for CA125 in 2 serous-tumor lines, for CA15.3 in 1 serous-tumor line, and for CEA in 3 lines of the mucinous subtype. This panel of human tumor xenografts could be a valuable tool to determine the potential usefulness of MAb-guided therapy in ovarian cancer.

Adenocarcinoma↗
PubMed1991

Pharmacokinetics and biodistribution of a new anti-episialin monoclonal antibody 139H2 in ovarian-cancer-bearing nude mice.

The new murine anti-episialin monoclonal antibody (mAb) 139H2 has been selected for its strong reactivity with a series of human ovarian cancer xenografts. In the present report we describe the characteristics of mAb 139H2 investigated in vitro as well as in vivo. Scatchard plot analysis using the human ovarian cancer cell line NIH:OVCAR-3 showed an affinity constant of 1 x 10(8) M-1 and the expression of 7 x 10(6) antigenic sites/cell. Reactivity with OVCAR-3 xenograft tissue was intense, localized at the cell membrane, heterogeneously distributed, and mainly detectable at the apical site of the cell. Administration of radiolabelled mAb 139H2 to nude mice bearing s.c. OVCAR-3 xenografts showed specific uptake in the tumour up to 9% of the injected dose/g. The maximum uptake in the tumour was retained for 3.5 days and mAb 139H2 cleared from the tumour with a half-life of 5.5 days. The half-life in blood was 50 h and no antibody-antigen complex formation could be detected. Poor uptake and no retention in episialin-negative WiDr colon cancer xenografts demonstrated specificity. Administration of an excess of an unlabelled irrelevant mAb did not influence the uptake in the OVCAR-3 xenografts or in other tissues. In contrast, tumour uptake decreased after addition of 300 micrograms or more unlabelled mAb 139H2 to a tracer dose of radiolabelled mAb 139H2. The uptake of mAb 139H2 in OVCAR-3 xenografts appeared inversely related to the tumour size.

Animals↗
PubMed1991

Tumour localisation with 131I-labelled human IgM monoclonal antibody 16.88 in advanced colorectal cancer patients.

Human IgM monoclonal antibody 16.88 recognised an intracellular antigen strongly expressed in colorectal cancer tissue in 51% of our patients. Tumour localisation was carried out with 185 MBq 131I-16.88 (8 mg) in 20 of these patients with advanced disease. In 16 patients (80%) immunoscintigraphy was positive in at least one organ site with disease. Of all sites, 55% could be visualized. In general, lesions less than 3 cm could not be detected. Sequential immunoscintigrams of liver metastases showed variable patterns. Initial "cold" lesions corresponded to liver metastases with poor blood supply as indicated by 99mTc-sulphur-colloid and 99mTc-HMPAO scintigraphy, respectively. The mean (S.D.) biological half-life (whole body clearance of radioactivity) was 37.6 (5.0) h. A second infusion of 131I-16.88 with the addition of high doses of unlabelled 16.88 could be done safely, but did not result in better visualisation of tumour lesions or affect radioactivity clearance from the body.

Adult↗