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Biomedical subjects

H J Haisma

Publications and source records attributed to H J Haisma.

68 records · Page 4Linked to original sources
PubMed1989

Localization and imaging of radiolabelled monoclonal antibody against squamous-cell carcinoma of the head and neck in tumor-bearing nude mice.

Nude mice carrying human squamous-cell carcinoma xenografts were given i.v. injections of radiolabelled monoclonal antibodies (MAbs). MAb E 48, which reacts with squamous-cell carcinomas, was labelled with 131I, while a second control MAb of similar immunoglobulin subclass was labelled with 125I. Both antibodies were injected simultaneously, then the mice were scanned with a gamma camera or their tissues were removed and antibody uptake was calculated as a percentage of the injected dose. Uptake of E 48 reached a peak value of 16%/g on day 3, while uptake of the control antibody was less than 1.8%/g. By 24 hr after injection tumor could be visualized without subtraction techniques. At days 3 and 7, only xenografts were visible on imaging. These findings suggest that E 48 is capable of high specificity in targeting isotopes to squamous-cell carcinomas in an experimental setting.

Animals↗
PubMed1988

Localization of radiolabelled F(ab')2 fragments of monoclonal antibodies in nude mice bearing intraperitoneally growing human ovarian cancer xenografts.

The biodistribution and pharmacokinetics of 2 monoclonal antibodies (MAbs) specific for ovarian carcinoma, OC125 and OV-TL3, were studied in nude mice bearing intraperitoneally (i.p.) growing human ovarian carcinoma xenografts of NIH:OVCAR-3. The ovarian carcinoma xenografts grew as non-adherent cells in ascites and as solid implants in the peritoneal cavity of injected mice. The biodistribution and pharmacokinetics were determined by measurement of radioactivity in tumor masses, ascites, blood and other tissues after intravenous (i.v.) and i.p. injection of radioiodinated F(ab')2 fragments of MAbs. The specificity of the observed tumor localization was then evaluated by comparing the uptake of the anti-ovarian carcinoma antibodies OC125 and OV-TL3 with the uptake of a radioiodinated non-ovarian carcinoma-specific MAb A2C6. The results of the study indicate that uptake of the anti-ovarian carcinoma antibodies was highest in the non-adherent tumor cells in the ascites after i.p. injection. The observed uptake was 85% injected dose/g for OV-TL3 and 22% injected dose/g for OC125. This compares to the observed antibody uptake of 9% injected dose/g for OV-TL3 and less than 1% injected dose/g for OC125 in solid tumor masses after i.p. injection. After i.v. injection, uptake of OC125 and OV-TL3 was less than 3% injected dose/g, both for nonadherent tumor cells and for solid tumor masses. The data support the conclusion that OV-TL3 is superior to OC125 and that i.p. administration of radiolabelled MAb F(ab')2 fragments is superior to their i.v. administration for immunotherapy of ovarian carcinoma.

Animals↗
PubMed1988

An assay for the detection of human anti-murine immunoglobulins in the presence of CA125 antigen.

A radioimmunoassay for the detection of human immunoglobulin response is described which is suitable for the screening of patients undergoing immunotherapy with murine monoclonal antibodies. The use and the sensitivity of the assay are illustrated in the case of patients undergoing diagnostic imaging for ovarian cancer with the monoclonal antibody, OC125. The method offers the distinct advantage of quantitating human anti-murine antibody in serum containing a high concentration of antigen recognized by the injected murine antibody. In addition, the assay may be generalized to screen patients undergoing immunotherapy with a variety of murine or other monoclonal antibodies.

Animals↗
PubMed1988

Biodistribution, pharmacokinetics and imaging of 131I-labelled OC125 in ovarian cancer.

Fifteen patients with or suspected of having ovarian carcinoma were injected intravenously (i.v.) or intraperitoneally (i.p.) with 131I-labelled OC125 F(ab')2. Radioimmunoscintigraphy after i.v. injection revealed 50% of the tumor sites. After i.p. injection all tumor sites were visualized, except in one case in which the antibody remained loculated because of adhesions. One patient with endometrial cancer showed no specific uptake of the antibody after i.p. injection. The serum half-life of the radiolabelled antibody after i.v. injection was 30 hr. After i.p. injection there was a slow appearance of radiolabelled antibody in the blood with a maximum level of 1.4% dose per liter at 24 hr after injection. Urinary excretion of the radiolabel was the same for both routes of administration, with 50% of the dose excreted in approximately 48 hr. Tumor uptake was slightly higher after i.p. injection. Liver and bone marrow uptake after i.p. injection were one-half of the uptake after i.v. injection.

Antibodies, Monoclonal↗
PubMed1988

Distribution and pharmacokinetics of radiolabeled monoclonal antibody OC 125 after intravenous and intraperitoneal administration in gynecologic tumors.

Radiolabeled monoclonal antibodies may be useful for radioimmunotherapy of gynecologic tumors. Iodine 131-labeled F(ab')2 fragments of a monoclonal antibody, OC 125, with specificity for ovarian carcinoma, were used to study the distribution and pharmacokinetics of this antibody in patients with gynecologic tumors. The radiolabeled antibody was injected intravenously or intraperitoneally into 10 patients suspected of having ovarian cancer. Blood and urine samples were used for pharmacokinetic studies, and biopsy specimens were examined for the uptake of antibody. The serum half-life of the labeled antibody was 30 hours after intravenous administration, with 20% of the injected dose per liter detected at 24 hours. After intraperitoneal injection, the appearance of antibody in serum was slow, with a maximum level of 1.4% of the injected dose per liter at 24 hours. Urinary excretion of the radiolabeled antibody was similar for intravenous and intraperitoneal administration, with approximately 50% of the injected dose excreted after 48 hours. Intraperitoneal administration of the radiolabeled antibody resulted in a higher uptake of antibody in the tumor and a lower uptake of antibody in normal tissues. On the basis of this limited study, intraperitoneal administration of radiolabeled antibody is preferred over intravenous administration for radioimmunotherapy of ovarian cancer.

Adult↗
PubMed1987

Antibody-antigen complex formation following injection of OC125 monoclonal antibody in patients with ovarian cancer.

Monoclonal antibody (MAb) OC125 binds to approximately 80% of epithelial ovarian cancers. Serum antigen, CA125, can be detected in these patients. 131I-OC125-F(ab')2 was injected into 5 ovarian carcinoma patients with preinjection serum levels of 150 to 9,000 CA125 U/ml. Patients received the antibody intravenously in doses ranging from 0.46 to 0.94 mg with a specific activity of approximately 2.5 mCi/mg 131I. The half-life in the circulation was approximately 30 hr and was independent of serum CA125 levels. Clearance of 131I from the circulation fitted an open, one-compartment mathematical model. Gel filtration chromatography revealed antibody-antigen complexes in sera 15 min after injection of the radiolabelled antibody. By 5 days after injection, the free form of OC125 antibody could not be detected in the serum. The rate of complex formation correlated well with the observed preinjection serum CA125 levels. This direct correlation was verified in vitro using purified CA125 antigen and radiolabelled OC125 F(ab')2 fragments. The specific effects of complex formation on tumor localization remains unclear. However, the presence of complexes should not be ignored, when planning for diagnostic imaging or immunotherapy with OC125 or other MAbs reacting with circulating antigen.

Adenocarcinoma↗
PubMed1987

Time-resolved immunofluorometric assay for the ovarian carcinoma-associated antigenic determinant CA 125 in serum.

A time-resolved immunofluorometric assay (IFMA) is described for quantifying the ovarian carcinoma-associated antigenic determinant CA 125 in human serum. Monoclonal antibody to CA 125 is immobilized onto a microtiter well, and the same antibody labeled with a europium chelate is used as a tracer. After the immunoreaction the bound portion of the labeled antibody is quantified by dissociating the Eu3+ in a fluorescence-enhancement solution and measuring its fluorescence with a time-resolved fluorometer. The detection limit of the IFMA is 1.5 arb. units/mL, being about the same as that of a commercially available immunoradiometric assay (IRMA) for CA 125 (1.4 arb. units/mL). The analytical range of the IFMA extends to 2000 arb. units/mL, whereas the range of the IRMA is 500 arb. units/mL. For 29 serum samples from ovarian-cancer patients measured simultaneously in the IFMA and IRMA, orthogonal regression analysis gave the equation CA 125 (IFMA) = 0.9937 CA 125 (IRMA) - 1.211 arb. units/mL (Syx = 6.8681, r = 0.9932). Apparently, the IFMA for CA 125 is a convenient alternative to the IRMA for CA 125 because of short counting times, the use of nonradioactive, stable reagents, and the much-extended measuring range. Additionally, the microtiter format should lend itself to more fully automated procedures in laboratories doing many such analyses.

Antigens, Neoplasm↗
PubMed1986

Higher ADCC of murine peritoneal cells after immunization with allogenic tumor cells as compared with stimulation by adriamycin, BCG, and thioglycolate.

Normal peritoneal cells or spleen cells from C57BL mice could not lyse SRBC in an ADCC assay. After intraperitoneal injection of Adriamycin, BCG or thioglycolate the ADCC of peritoneal cells toward antibody-coated SRBC was elevated to 30% in contrast to the ADCC of spleen cells. However, peritoneal cells but not spleen cells of mice immunized with allogenic tumor cells (DBA SL2) showed ADCC levels at least two times higher than the levels observed after stimulation by other agents. Maximal ADCC levels (55.8%) were observed 10 to 15 days after immunization. Direct cytotoxicity towards SRBC increased to a maximum of 17.7% at 9 days after immunization. The effector cells in this system are thought to be macrophages, for ADCC activity was only present in the plastic-adherent cell fraction. Cell to cell contact was necessary for ADCC to occur; nonsensitized erythrocytes were not lysed when added to a mixture of effector cells and sensitized erythrocytes. Concentrations of antibody of 1 pg/ml were sufficient to induce ADCC, and effector cell to target cell ratios could be as low as 0.05. The finding that macrophages of mice immunized with allogenic tumor cells exhibit higher ADCC levels than macrophages elicited in other ways can contribute to the investigation of combined cancer therapy with antibodies and biological response modifiers.

Animals↗
PubMed1986

Iodination of monoclonal antibodies for diagnosis and radiotherapy using a convenient one vial method.

We have developed a convenient system that can be used to iodinate monoclonal antibodies for diagnosis or therapy. A vial, previously coated with 1,3,4,6-tetrachloro-3a, 6a-diphenyl glycouril (iodogen), is used as a reaction vessel. Iodination and separation of bound and free iodide, using AG1-X8 ion exchange resin, are both accomplished in this vial. We found 90 +/- 4% of the iodide which was added was incorporated, respectively, into each of four different monoclonal antibodies evaluated. Approximately 90% of labeled antibody was recovered in each case. The monoclonal antibody OC125 was labeled to specific activities up to 25 mCi/mg. Immunoreactivities of 82 +/- 2% using 125I and 66 +/- 5% using 131I were achieved. As the radioiodination is done in one sealed vial and takes less than 15 min, this procedure is safe and can be performed in any nuclear medicine laboratory. The final product, which is sterile and apyrogenic, is suitable for diagnostic and radiotherapeutic applications.

Antibodies, Monoclonal↗
PubMedDate not supplied

Cationic polymeric gene delivery of beta-glucuronidase for doxorubicin prodrug therapy.

BACKGROUND: An approach to improve current chemotherapy is the selective transduction of tumor cells with suicide genes to sensitize these cells to prodrugs of cytostatic agents. METHODS: In this study, gene transfer was accomplished with the cationic polymer poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA), able to condense plasmid-DNA by electrostatic interaction. OVCAR-3 cells were transfected with plasmids encoding E. coli-derived or human beta-glucuronidase and the transfection efficiency and inhibition by serum was determined. Next, we measured the sensitivity of OVCAR-3 cells transiently expressing beta-glucuronidase to the glucuronide prodrug of doxorubicin (DOX-GA3) or to doxorubicin. RESULTS: OVCAR-3 cells were efficiently transfected with a plasmid encoding E. coli-derived beta-glucuronidase. The degree of transfection (30% of cells) was higher than that achieved with commercially available cationic lipids (DOTAP, Lipofectamine) without inhibition by serum. OVCAR-3 cells transiently expressing beta-glucuronidase were equally sensitive to the glucuronide prodrug of doxorubicin (DOX-GA3) or to doxorubicin itself, indicating complete conversion of prodrug to drug. Similar studies were performed with the plasmid encoding for human beta-glucuronidase, which is likely to be less immunogenic. Also in this case, OVCAR-3 cells showed an increased sensitivity to the prodrug DOX-GA3, although less pronounced than when the bacterial enzyme was used. A strong bystander effect was observed when OVCAR-3 cells transfected with beta-glucuronidase were mixed with non-transfected cells at different ratios. Complete tumor cell growth inhibition was already observed when only 15% of the cells expressed the activating enzyme. CONCLUSION: These studies suggest that beta-glucuronidase gene therapy using PDMAEMA as a carrier system and DOX-GA3 as the prodrug has a potential application in cancer gene therapy.

Antibiotics, Antineoplastic↗
PubMedDate not supplied

Epidermal growth factor receptor targeting enhances adenoviral vector based suicide gene therapy of osteosarcoma.

BACKGROUND: Despite improvements in the treatment of osteosarcoma (OS) there are still too many patients who cannot benefit from current treatment modalities. Therefore, new therapeutic approaches are warranted. Here we explore the efficacy of targeted adenoviral based suicide gene therapy. METHODS AND RESULTS: Immunohistochemistry and FACS analysis detected low or absent expression levels of the primary adenovirus receptor CAR on human primary OS and human OS cell lines. These results predict a low infection efficiency and thus a reduced therapeutic effect. Targeting the adenoviruses to another receptor highly expressed on OS could overcome this limitation. We found epidermal growth factor receptor (EGFR) to be widely expressed on primary OS. Immunohistochemistry on primary tumor samples and FACS analysis on primary short-term cultures and four OS cell lines showed that EGFR was consistently expressed. The recombinant bispecific single-chain antibody 425-s11 redirects adenoviral vectors towards the EGFR. Adenovirus transduction experiments in the presence or absence of 425-s11 showed significantly enhanced gene transfer with the targeted adenoviral vector compared with the native vector (OS cell lines 2.5 to 7.2 times enhanced gene transfer and OS primary short term cultures 1.7 to 10 times enhanced gene transfer). On this basis, targeted suicide gene therapy experiments with AdCMVHSV-TK in combination with ganciclovir were performed. These experiments demonstrated up to 3.5-fold enhanced kill of OS cell lines and primary short-term cultures by the EGFR targeted vector. CONCLUSIONS: Suicide gene therapy with adenovirus targeted towards EGFR may have favorable therapeutic characteristics for future gene therapy applications in OS.

Adenoviridae↗
PubMedDate not supplied

Improved characteristics of a human beta-glucuronidase-antibody conjugate after deglycosylation for use in antibody-directed enzyme prodrug therapy.

Antibody-directed enzyme prodrug therapy (ADEPT) aims at the specific activation of relatively nontoxic prodrugs into active drugs at the tumor site. One of the enzymes described to be useful in ADEPT is human beta-glucuronidase (GUS), which is expected to have low immunogenicity in patients. A major obstacle for the use of GUS, however, is its rapid glycan-specific hepatic clearance. The carbohydrates of GUS have been modified by subsequent treatment with NaIO4 and NaBH4 to improve its retention in the circulation. The modification of GUS did not decrease the enzyme activity. In vitro it was demonstrated that a conjugate prepared with a pancarcinoma specific monoclonal antibody (mAb) 323/A3 and the modified enzyme (mGUS), when bound to tumor cells, was capable of complete prodrug activation. In vivo, the 323/A3-mGUS conjugate was cleared faster from the circulation of BALB/c mice (t1/2 = 9 h) than mAb 323/A3 (t1/2 = 32 h), but it was retained in the circulation much longer than an immunoconjugate prepared with native GUS (t1/2 = 24 min). In nude mice bearing subcutaneous OVCAR-3 tumors the distribution of 323/A3-mGUS was qualitatively comparable to that of mAb 323/A3. The 323/A3-mGUS conjugate showed specific localization in the tumor but to a lesser extent than mAb 323/A3 (2.7% vs 6.4% injected dose per gram at 1 day after iv injection). A favorable tumor-to-blood ratio of > 2 was observed for the conjugate at 7 days after administration, which is necessary for tumor-specific prodrug activation.

Animals↗
PubMedDate not supplied

Distribution and kinetics of 131I-labeled human IgM monoclonal antibody 16.88 in patients with advanced colorectal cancer.

Sequential immunoscintigrams were used to describe the relative distribution and kinetics of 8 mg 131I-labeled human IgM monoclonal antibody 16.88 in 20 patients with colorectal cancer. The results show that the initial activity was higher and the clearance rate was faster (P < 0.05) from the left ventricle and liver than from most organs. In bone marrow the reverse was observed (P < 0.05). The biological half-life of 131I(-16.88) in tumor tissue (range 35.4-47.5 h) was longer (P < 0.01) than that in normal tissue (30.2-41.9 h). The image contrast ratio between liver metastases and background increased from 0.8 to 1.3 and for lesions outside the liver from 1.1 to 1.6. The estimated effective dose equivalent was 0.12 mSv/MBq. A second infusion 2 weeks after the first with the addition of unlabeled 16.88 up to 1000 mg for improvement of tumor tissue uptake was not of clinical relevance.

Antibodies, Monoclonal↗