Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Immunoconjugates”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 559 records · Page 31Linked to original sources
PubMedDate not supplied

Experimental treatment of malignant gliomas with human monoclonal antibody-drug conjugates.

This study was designed to determine whether the monoclonal antibody-drug conjugates are more potent than the free drugs in killing human glioma cells in vitro and in vivo. The anticancer drugs doxorubicin (DXR) and 4'-epi-doxorubicin (epi-DXR) were separately conjugated to the human monoclonal antibody (mAb) CLNIgG, which binds strongly to human malignant glioma cells. The cytotoxic activity of the mAb-drug conjugates was assessed by a 3H-thymidine assay in vitro. The efficacy, biodistribution and autography of the immunoconuugates were examined using the subcutaneous glioma model (nude mouse). The epi-DXR-CLNIgG conjugate was found to be 11 times more potent than free epi-DXR in killing glioma cells in vitro, and epi-DXR-CLNIgG clearly achieved the most favorable antitumor effects. A biodistribution study using [14-14C]DXR-CLNIgG at the conjugate indicated that the immunoconjugates delivered DXR to glioma tissues at least five times more than the free DXR alone in nude mice without increasing the concentration in other tissues. An autoradiographic study also showed good accumulation of the antibody-drug conjugate in the subcutaneously transplanted glioma. Thus, the human monoclonal antibody-drug conjugates constitute a potential new approach for the treatment of malignant gliomas.

Animals↗
PubMedDate not supplied

Epidermal growth factor receptor-dependent cytotoxic effect of anti-EGFR antibody-ribonuclease conjugate on human cancer cells.

We have conjugated the murine monoclonal antibody (528) against the human epidermal growth factor receptor (EGFR) to mammalian pancreatic ribonuclease (RNase) via N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP) and 2-iminothiolene (2-IT). The conjugate showed dose-dependent cytotoxicity against EGFR-producing squamous cancer cells (A431, TE8, TE5, Ca9-22) and no detectable cytotoxicity against EGFR-deficient small-cell lung cancer cells (H69). The cytotoxicity of the conjugate was positively correlated with the EGFR numbers of each cell line. The addition of excess 528 antibody to the medium protected A431 cells from the conjugate cytotoxicity. This immunoconjugate might be useful for targeted treatment of squamous cell carcinomas hyperexpressing EGFR.

Animals↗
PubMed2001

[Inhibition of the growth of hepatoma and hepatic metastasis by pingyangmycin conjugated with Fab' fragment of monoclonal antibody].

OBJECTIVE: To develop an immunoconjugate with inhibitory effect on the growth of hepatoma and hepatic metastasis of tumor by linking Fab' fragment of monoclona antibody (McAb) to pingyangmycin (PYM). METHODS: Monoclonal antibody Fab' fragment was obtained by enzymolysis with pepsin and DTT reduction. Linking of the Fab' fragment and PYM was mediated by dextran T40. Indirect ELISA, TTC bacteriostatic titer test, clonogenic assay and animal models transplanted with tumor were used to assess the biological activities and antitumor effects of Fab' PYM conjugate within and without the bodies of 10 mice. RESULTS: The Fab' PYM conjugate showed immunoreactivity to BEL7402, hepatoma 22 (H22) and HT29 cells, but no reaction to KB cells. The bacteriostatic activity of PYM in the conjugate was 15% as much as that of free PYM. The 50% inhibitory doses (IC50) of Fab'PYM conjugate to BEL7402, HT29 cells and KB cells were 0.02 micromol/L, 0.08 micromol/L and 0.50 micromol/L respectively. Given intravenously, 10 mg/kg x 6, Fab' PYM conjugate and PYM suppressed the growth of hepatoma 22 by 86% and 62% respectively. Given intraperitoneally, 10 mg/kg x 4, Fab' PYM and PYM decreased the hepatic metastasis of colon carcinoma 26 by 91% and 62% respectively. CONCLUSION: Fab' PYM conjugate is more effective in combating hepatoma and hepatic metastasis of tumor than free PYM.

Animals↗
PubMed2002

[Monoclonal antibody for cancer treatment].

Antibodies have for many decades been viewed as ideal molecules for cancer therapy. Although promising from the start, it has taken much of more than two decades to reach the level of clinical application. Genetic engineering of antibodies; that is novel technologies for chimeric or humanizing monoclonal antibodies, has greatly advanced their utility in molecular targeting therapies, and in the past four years some therapeutic monoclonal antibodies for hematologic malignancies and solid tumors, such as Rituximab for B-cell lymphoma and Trastuzumab for metastatic breast cancer, have provided sufficient efficacy and safety to support regulatory approval from the U.S. Food and Drug Administration. They were subsequently approved by the Japanese Ministry of Health, Labour and Welfare in 2001. Many molecular biological and immunological studies have revealed the targeting properties of the host immune system and the biological mechanism of cancer cells for a more specific anticancer effect. Many clinical trials of monoclonal antibodies as a single agent, or in combination protocol with current standard chemotherapy or immunoconjugates have shown promise in the treatment of specific diseases. Furthermore, novel antibody designs and improved understanding of the mode of action of current antibodies lend great hope to the future of this therapeutic approach. The accumulating results from many basic, clinical and translational studies may lead to more individualized therapeutic strategies using these agent directed at specific genetic and immunologic targets.

Antibodies, Monoclonal↗
PubMed2003

In vivo evaluation of pretargeted 64Cu for tumor imaging and therapy.

UNLABELLED: Pretargeting involves administration of a tumor-targeting monoclonal antibody (mAb) covalently linked to a molecule having a high-affinity binding site for a rapidly distributed radiolabeled effector molecule. The aim of this study was to compare pretargeting to a conventionally labeled antibody for tumor targeting of the intermediate-lived radionuclide (64)Cu, which has shown promise for PET imaging and radioimmunotherapy of cancer. METHODS: DOTA-biotin (where DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid) and the intact immunoconjugate DOTA-NR-LU-10 were labeled to high specific activities with (64)Cu, and the serum stabilities and target binding capabilities of each agent were assayed in vitro. Nude mice bearing SW1222 human colorectal carcinoma xenografts were administered (64)Cu-DOTA-biotin, with and without pretreatment with the mAb-streptavidin conjugate NR-LU-10/SA and the synthetic clearing agent Biotin-GalNAc(16), or injected with (64)Cu-DOTA-NR-LU-10. Biodistributions of both agents were obtained from 5 min to 48 h after injection. RESULTS: Both (64)Cu-DOTA-biotin and (64)Cu-DOTA-NR-LU-10 were 100% stable in serum in vitro. (64)Cu-DOTA-biotin exhibited >98% specific binding to immobilized streptavidin, whereas the immunoreactivity of (64)Cu-DOTA-NR-LU-10 averaged nearly 80%. Biodistributions in SW1222-bearing mice showed that NR-LU-10/SA-pretargeted (64)Cu-DOTA-biotin attained a peak tumor uptake of 18.9 percentage injected dose per gram (%ID/g) at 1 h, with concomitant rapid disappearance from blood and renal excretion. In the absence of pretargeting, (64)Cu-DOTA-biotin had very similar biodistribution and clearance properties, except with extremely low nonspecific tumor uptake. In contrast, (64)Cu-DOTA-NR-LU-10 reached 80.3 %ID/g in tumor tissue, after 48 h, whereas blood clearance was considerably slower than pretargeted (64)Cu-DOTA-biotin. Comparison of the time-activity curves for tumor uptake and blood clearance of pretargeted (64)Cu and the (64)Cu-labeled antibody revealed that the maximum tumor accumulations of radioactivity were similar for each agent, 17.9 percentage injected activity per gram (%IA/g) and 20.7 %IA/g, respectively. However, the tumor-to-blood ratio of areas under the curves was 14 times higher for pretargeted (64)Cu-DOTA-biotin because of the substantial increase in blood clearance of the small effector molecule. CONCLUSION: The extremely rapid tumor uptake and blood clearance of pretargeted (64)Cu-DOTA-biotin should afford markedly superior PET imaging contrast and therapeutic efficacy, compared with conventionally labeled (64)Cu-DOTA-NR-LU-10. Further comparison of the therapeutic efficacy, toxicity, and dosimetry of these 2 agents is warranted.

Animals↗
PubMed2003

[Experimental study of combined target treatments using PYM-BAC5 and 131I-BAC5 to nasopharyngeal carcinoma].

BACKGROUND & OBJECTIVE: Combined therapy has been advocated for modern tumor treatment; the combined target therapy is a valuable research direction. Based on the previous research of nasopharyngeal carcinoma (NPC) radioimmunotherapy, this experiment was designed to develop two immunoconjugates of the monoclonal antibody BAC(5):PYM-BAC(5) and (131)I-BAC(5), and to assess the inhibition effects of their combined treatment on the NPC CNE-2 cells cultured in vitro. METHODS: Dextran T40 was used as media to link PYM and BAC(5). The conjugate PYM-BAC(5) was identified by testing its immunoactivity and the inhibition to mycobacterium. BAC(5) was labeled with (131)I by Chloramin-T method. Five experimental groups were set up:(1)PYM-BAC(5) group, (2)free PYM group, (3)(131)I-BAC(5) group, (4)(131)I-mIgG group, (5)the combined target treatment group ( (131)I-BAC(5)+PYM-BAC(5)). The antitumor effects of the five groups were assessed with MTT method. RESULTS: The 50% inhibition doses(IC(50)) of PYM-BAC(5) group and PYM group were 46.57 microg/ml and 316.7 microg/ml, respectively. The IC(50) of (131)I-BAC(5) group and (131)I-mIgG group to CNE2 were 4.42 x 10(5) Bq/ml and >11.1 x 10(5) Bq/ml,respectively. In the combined target treatment group(PYM-BAC(5)+(131)I-BAC(5)),the IC(50) of PYM-BAC(5) was 7.01 microg/ml and of (131)I-BAC(5) was 0.54 x 10(5) Bq/ml, which much less than other separate treatment groups. CONCLUSION: The inhibition effects of the target treatment ((131)I-BAC(5) and PYM-BAC(5)) on the NPC CNE-2 cells are stronger than non-target treatment (free PYM and (131)I-BAC(5)). The combined target treatment of the two immune ((131)I-BAC(5)+PYM-BAC(5)) conjugates gets stronger inhibition effects than their separate treatment.

Antibiotics, Antineoplastic↗
PubMed2005

Biodistribution of yttrium-90-labeled anti-CD45 antibody in a nonhuman primate model.

PURPOSE: Radioimmunotherapy may improve the outcome of hematopoietic cell transplantation for hematologic malignancies by delivering targeted radiation to hematopoietic organs while relatively sparing nontarget organs. We evaluated the organ localization of yttrium-90-labeled anti-CD45 ((90)Y-anti-CD45) antibody in macaques, a model that had previously predicted iodine-131-labeled anti-CD45 ((131)I-anti-CD45) antibody biodistribution in humans. EXPERIMENTAL DESIGN: Twelve Macaca nemestrina primates received anti-CD45 antibody labeled with 1 to 2 mCi of (90)Y followed by serial blood sampling and marrow and lymph node biopsies, and necropsy. The content of (90)Y per gram of tissue was determined by liquid scintillation spectrometry. Time-activity curves were constructed using average isotope concentrations in each tissue at measured time points to yield the fractional residence time and estimate radiation absorbed doses for each organ per unit of administered activity. The biodistribution of (90)Y-anti-CD45 antibody was then compared with that previously obtained with (131)I-anti-CD45 antibody in macaques. RESULTS: The spleen received 2,120, marrow 1,060, and lymph nodes 315 cGy/mCi of (90)Y injected. The liver and lungs were the nontarget organs receiving the highest radiation absorbed doses (440 and 285 cGy/mCi, respectively). Yttrium-90-labeled anti-CD45 antibody delivered 2.5- and 3.7-fold more radiation to marrow than to liver and lungs, respectively. The ratios previously observed with (131)I-anti-CD45 antibody were 2.5-and 2.2-fold more radiation to marrow than to liver and lungs, respectively. CONCLUSIONS: This study shows that (90)Y-anti-CD45 antibody can deliver relatively selective radiation to hematopoietic tissues, with similar ratios of radiation delivered to target versus nontarget organs, as compared with the (131)I immunoconjugate in the same animal model.

Animals↗
PubMed1995

Cellular processing of copper-67-labeled monoclonal antibody chCE7 by human neuroblastoma cells.

Monoclonal antibody chCE7, an internalizing neuroblastoma-specific chimeric antibody, was derivatized with the macrocyclic amine ligand 4-[(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl] benzoic acid tetrahydrochloride and labeled with the potential therapeutic nuclide 67Cu. Using pulse labeling and an acid elution endocytosis assay, 67Cu-chCE7 was found to be internalized into human neuroblastoma (SKN-AS) cells at a similar rate and to a similar extent as 125I-labeled chCE7. Uptake of 67Cu-chCE7 and 125I-chCE7 into the acid stable (intracellular) pool proceeded with similar kinetics during the first 2 h of internalization. However, in contrast to 125I-chCE7-loaded cells, at later times intracellular radioactivity kept increasing in the case of 67Cu-chCE7-loaded cells. It was shown that this effect is due to the intracellular accumulation of a low M(r) degradation product consisting of the 67Cu-4[(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl] benzoic acid complex, possibly with a short peptide attached to it. Degradation of both 125I-chCE7 and 67Cu-chCE7 was inhibited by chloroquine, indicating endosomal or lysosomal degradation, and a 43,000 M(r) fragment was found to be the major high M(r) degradation product in both cases. Although at times between 4 and 6 h of internalization intracellular breakdown of 67Cu-chCE7 was found to proceed more slowly, the major difference between the two immunoconjugates resides in the prolonged cellular retention of the 67Cu-chCE7 metabolite.

Antibodies, Monoclonal↗
PubMed1996

[Application of tumor marker for immunotargeting therapy of cancer].

For many years, attempts have been made to utilize the monoclonal antibody against tumor markers for diagnostic purposes. On the other hand, studies with various form of immunoconjugate have demonstrated some therapeutic promise. In this paper, the ideal tumor marker for immunotargeting therapy will be discussed. Results of clinical trials of radioimmunoconjugates, immunotoxin and chemoimmunoconjugates will be reviewed and prospects of these new approaches for the treatment of cancer patients will be presented.

Animals↗
PubMedDate not supplied

Antibody-mediated gene delivery for B-cell lymphoma in vitro.

The targeted introduction of therapeutic genes into malignant cells based on receptor mediated endocytosis of ligand-DNA conjugates recently was established as a transfection system and provides a promising strategy for cancer therapy. Antiidiotype antibodies could be of particular interest for this approach because their immunoglobulin receptor idiotypes represent highly specific tumor markers. Their safe and specific applicability in vivo, alone or as immunotoxins, has been proven in clinical trials for passive immunotherapy and vaccination strategies. For these reasons we have explored the utility of antiidiotype antibodies for gene delivery systems using the reporter genes beta-galactosidase and luciferase. Two monoclonal antibodies, SIC5 and 5D10, specific for B-lymphoma cell lines, which represent models for murine plasmacytoma (38C13) and human non-Hodgkin's lymphoma (SU-DHL-4) have been covalently linked to polylysine via the heterobifunctional cross-linker SPDP. Highly efficient uptake and internalization of the immunoconjugates have been shown by fluorescence microscopy and fluorescence-activated cell sorting (FACS) analysis. Successful transfections have been shown at the RNA and the reporter gene level (beta-galactosidase, luciferase) using different promoter/enhancer systems. Beta-galactosidase activity was detected by flow cytometry (FACS-gal) analysis for both cell lines, and SU-DHL-4 cells showed significant luciferase activity.

Animals↗
PubMed1998

Effects of linker chemistry on the pharmacokinetics of radioimmunoconjugates.

Radiolabeled monoclonal antibodies reactive with tumor-associated antigens can selectively deliver cytotoxic or diagnostic isotopes to malignant cells in vivo. To achieve maximum retention of radiolabel in tumor and a more rapid clearance of radioisotope from normal tissues, six linker immunoconjugates were evaluated in studies using nude mice and beagle dogs. All radioimmunoconjugates contained a mouse monoclonal IgG (QCI) reactive with human ferritin. Different chemical linkages were inserted between immunoglobulins and the radiolabeled chelate (DTPA). Three linkers (ITCB, DSS and BSOCOES) were stable in in vitro and in vivo studies. Three linkers (EGS, DST and DSP) were labile in in vitro and in vivo studies. Indium-111 labeled antiferritin-containing ITCB or DSS linker showed high uptake in human hepatoma xenografts in nude mice. In addition, long blood half-lives and higher normal liver uptakes were noted. Studies of whole body retention of radioimmunoconjugates showed approximately three-fold faster elimination of radioimmunoconjugates containing a labile linker (EGS). EGS linker is the labile linker with the highest therapeutic ratio: higher tumor uptake, but low normal liver uptake and a shortened blood half-life of the radioimmunoconjugate. The differences in normal tissue uptake (liver) between EGS and ITCB were confirmed in beagle dogs. Urine elimination studies and incubation or radioimmunoconjugates in serum or tissue homogenates of tumor, liver or muscle, showed that enzymes in serum and liver homogenates were able to cleave the labile linkers, which led to a more rapid elimination of low molecular weight radioactive metabolites in urine. The metabolism of linker radioimmunoconjugates in tumor was less effective. The labile linker DSP appears less useful because sulphydryl groups that are generated by cleavage of cause higher uptake radioactivity in normal kidney. Biodistribution studies in nude mice were confirmed by serial immunoscintigraphy studies on individual mice. The immunoscintigraphy studies are semi-quantitative only, but enable the use of lower numbers of experimental animals. This is of particular significance in large experimental animals such as beagle dogs. The labile linker approach can reduce normal tissue radiation exposure. The study also provides an example of preclinical optimization of radioimmunoconjugates. Continued use of the appropriate preclinical animal models will accelerate more successful applications of radioimmunoconjugates in cancer patients.

Animals↗
PubMed1998

Combined fluorescent and gold immunoprobes: reagents and methods for correlative light and electron microscopy.

Immunoprobes which incorporate both a fluorescent label and a 1.4 nm gold cluster compound were prepared by covalent conjugation to Fab' antibody fragments of the Nanogold cluster label followed by a fluorescent moiety. These new immunoconjugates allow the collection of two complementary sets of data, from fluorescence and electron microscopy, from a single labeling experiment. By using Fab' fragments, the entire probe is smaller than a whole IgG molecule. A simple fluorescence assay was used to investigate the fluorescence properties of the new probes. They were used to localize the pre-mRNA splicing factor SC35 in the HeLa cell nucleus by both fluorescence and electron microscopy, and also for labeling leukocyte microtubules; labeling was imaged using fluorescence microscopy and, after silver enhancement, by a variety of optical methods and by electron microscopy. Combined Nanogold and Texas Red, Cy3, Lissamine Rhodamine B, and AMCA probes were also prepared, and in preliminary experiments show similar properties to the combined fluorescein and gold cluster probes. The fluorescent and gold cluster probes enable a new degree of correlation between fluorescence and electron microscopy, and may also be used to check labeling of specimens before processing for electron microscopy.

Cell Nucleus↗
PubMed1997

Enhancement of 67Cu-2IT-BAT-LYM-1 therapy in mice with human Burkitt's lymphoma (Raji) using interleukin-2.

BACKGROUND: Lymphomas have been shown to be responsive to 131I immunoconjugates in studies conducted in mice and patients. We have observed that copper 67 (67Cu)-labeled Lym-1 remains in lymphomatous tissue longer than 131I-Lym-1 and, consequently, results in higher absorbed radiation doses to tumors. In addition, recombinant interleukin-2 (rIL-2) has been reported to increase tumor uptake of radiolabeled antibody. Therefore, we examined the efficacy of 67Cu-labeled Lym-1 and the ability of rIL-2 to enhance this efficacy in athymic mice implanted with Raji xenografts. METHODS: 6[p-(bromoacetamido) benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N', N'',N'''-tetraacetic acid (BAT) was conjugated to Lym-1 via 2-iminothiolane (2IT) to prepare 2IT-BAT-Lym-1, which was labeled with 67Cu. Mice with Raji xenografts were treated with 335-500 microCi (12.4-18.0 MBq) of 67Cu-2IT-BAT-Lym-1 with or without 48,000-144,000 IU of rIL-2 once or were treated b.i.d. for 5 days beginning simultaneously with 67Cu-2IT-BAT-Lym-1. Mouse weight, blood counts, and mortality were monitored to assess toxicity, and tumor size was measured to assess efficacy. In addition, groups of mice were sacrificed to assess the biodistribution of 67Cu-2IT-BAT-Lym-1 with and without rIL-2. RESULTS: In mice treated with 335 microCi of 67Cu-2IT-BAT-Lym-1 alone, 28% of tumors were cured. When 48,000 IU of rIL-2 were added, 50% were cured. The overall response-rate was 50% for both regimens. In mice treated with 400 microCi of 67Cu-2IT-BAT-Lym-1 alone, 42% responded, all of which were cured. When 48,000 IU of rIL-2 were added, 77% of tumors responded, and 38% were cured. Larger or multiple doses of rIL-2 did not result in additional therapeutic enhancement. The tumor uptake and radiation dose after 67Cu-2IT-BAT-Lym-1 were about two times greater when a single dose of rIL-2 was added: This may be the basis for enhanced therapeutic efficacy. Mortality was not altered for 335 microCi or 400 microCi doses of 67Cu-2IT-BAT-Lym-1 by rIL-2 nor were other toxicity parameters. Mortality was increased at 500 microCi by the addition of rIL-2. CONCLUSIONS: 67Cu-2IT-BAT-Lym-1 provided a therapeutic and frequently curative dose of radiation to tumored mice at tolerated doses. The therapeutic effectiveness of 67Cu-2IT-BAT-Lym-1 may have been enhanced by rIL-2.

Animals↗
PubMed1997

Escalating protein doses of chimeric monoclonal antibody MOv18 immunoglobulin G in ovarian carcinoma patients: a phase I study.

BACKGROUND: Successful first-line treatment of ovarian cancer does not incite cure. Recurrent disease often shows an increased resistance to chemotherapeutic agents. Therefore, other treatment modalities, like (radio)immunotherapy using tumor-associated monoclonal antibodies, should be considered. Chimeric MOv18 (c-MOv18) localizes well in ovarian carcinoma tissue. We investigated the safety of a single intravenous (i.v.) infusion of increasing doses of c-MOv18 in ovarian carcinoma patients. METHODS: Fifteen patients received c-MOv18 (from 5 mg to 75 mg). Safety was determined by recording vital signs; by hematological, biochemical, and urinary analyses; and by the human-antichimeric antibody (HACA) response. Five patients received c-MOv18 labeled with a tracer dose of iodine-131 to analyze the pharmacokinetics and biodistribution in blood, urine, and tissue biopsies at surgery. RESULTS: Administration of c-MOv18 IgG was uneventful. No significant changes in hematological, biochemical, or urine profiles were noted at any time postinjection (p.i). Starting with a dose of 50 mg, all patients experienced side effects, like fever, headache, and nausea/vomiting, maximally Grade II (World Health Organization toxicity scale). No HACA response was found up to 12 weeks p.i. The mean elimination half-life after infusion of 30-75 mg c-MOv18 was significantly higher compared with infusion of 1 mg. Absolute amount of c-MOv18 in carcinoma tissue increased with increasing c-MOv18 doses. CONCLUSIONS: Intravenous administration of c-MOv18 IgG in a dose up to 75 mg is safe, inducing only minor side effects at doses of 50 mg or higher. In view of the characteristics of c-MOv18, this antibody might be applicable as an unmodified antibody or as an immunoconjugate in the treatment of ovarian carcinomas.

Adult↗
PubMed2000

From the Laboratory to the Clinic: A Retrospective on Fully Synthetic Carbohydrate-Based Anticancer Vaccines Frequently used abbreviations are listed in the appendix.

This review provides an account of our explorations into oligosaccharide and glycoconjugate construction for the creation and evaluation of vaccines based on carbohydrate-centered tumor antigens. Our starting point was the known tendency of transformed cells to express selective carbohydrate motifs in the form of glycoproteins or glycolipids. Anticancer vaccines derived from carbohydrate-based antigens could be effective targets for immune recognition and attack. Obtaining significant quantities of such structures from natural sources is, however, extremely difficult. With the total synthesis of tumor-associated carbohydrate antigens accomplished, we began to evaluate at the clinical level whether the human immune system can respond to such fully synthetic antigens in a focused and useful way. Toward this goal, we have merged the resources of chemistry and immunology in an attack on the problem. The synthesis and immunoconjugation of various tumor-associated carbohydrate antigens and the results of such constructs in mice vaccinations will be described. For fashioning an effective vaccine, conjugation to a suitable immunogenic carrier was necessary and conjugates of KLH (keyhole limpet cyanin) have consistently demonstrated the relevant immunogenicity. Preclinical and clinical studies with synthetic conjugate carbohydrate vaccines show induction of IgM- and IgG-antibody responses. Another approach to anticancer vaccines involves the use of clustered glycopeptides as targets for immune attack. Initial attention has been directed to mucin related O-linked glycopeptides. Synthetic trimeric clusters of glycoepitopes derived from the Tn-, TF- and Lewis(y)-antigens, appropriately bioconjugated, have been demonstrated to be immunogenic. The hope is that patients immunized in an adjuvant manner with synthetic carbohydrate vaccines would produce antibodies reactive with cancer cells and that the production of such antibodies would mitigate against tumor spread, thereby enabling a more favorable survival and "quality of life" prognosis.

Journal Article↗
PubMed1994

Potential for recombinant immunoglobulin constructs in the management of carcinoma.

BACKGROUND: Numerous monoclonal antibodies (MoAb) have been developed and currently are being evaluated in both diagnostic and therapeutic clinical trials. Despite the major advances fostered by MoAb technology, several limitations inherent to the use of MoAb exist. For example, MoAb may not have the desired plasma pharmacokinetics and metabolic properties, and they may be immunogenic, thus reducing the possibility of numerous administrations. METHODS: Recombinant DNA technology is used to develop (1) mouse-human chimeric antibodies in which the constant region of a murine antibody is replaced with the human constant region, (2) chimeric antibodies with domain-deletions or alterations in glycosylation, and (3) sFv molecules, i.e., recombinant proteins composed of a VL amino acid sequence of an immunoglobulin tethered to a VH sequence by a designed peptide. RESULTS: This article reviews some of the genetic modifications that can be made with recombinant or chimeric immunoglobulin forms; two anti-TAG-72 MoAb, B72.3 and CC49, are used as examples. The immunoglobulin molecules that have been generated include those with alterations of subclass, domain deletions, and glycosylation, as well as those sFv molecules that have been prepared. The immunochemical and biologic properties of these novel immunoglobulin forms are described. CONCLUSIONS: Recombinant DNA technology makes feasible the development of novel immunoglobulin forms. These genetic modifications may result in more useful diagnostic reagents and in the production of more stable immunoconjugates with the characteristics of more efficient tumor cell killing.

Animals↗
PubMed1994

Overview of clinical radioimmunodetection of human tumors.

The role of radioimmunodetection in the detection of cancer has been established through the development of high affinity immunoconjugates and recent improvements in radiochemistry. Advances in imaging techniques, particularly single-photon emission computed tomography and image registration, also have dramatically improved the sensitivity and accuracy of tumor detection. Molecular engineering of immune constructs provides promise of enhanced tumor localization properties and reduced immunogenicity, allowing repeated studies to be performed. The role of radioimmunodetection in the evaluation of cancer patients will increase in importance in the future.

Adult↗
PubMed1995

Tumor antigens in astrocytic gliomas.

Gliomas affect 15,000 to 17,000 Americans every year and carry a dismal prognosis. The potential of immunologically mediated diagnosis and therapy, although greatly enhanced since the advent of monoclonal antibodies, has not been fully realized due to significant problems, most especially the challenge of identifying antigenic molecules specific to glial tumors. Other problematic issues include antigen-associated factors such as heterogeneity, modulation, shedding, and cross-reactivity with normal cells, and factors associated with therapeutic agent delivery, typically variable tumor perfusion and unfavorable diffusional forces in tumor microenvironment. An understanding of these problems called for the delineation of operationally specific antigens (tumor-associated antigens not expressed by the normal central nervous system) combined with the use of compartmental therapeutic approaches to increase the specificity of therapy. Numerous antigens have been identified and are classified as extracellular/matrix-associated, membrane-associated, and intracellular antigens. Nevertheless, only a few have been demonstrated to be of significant therapeutic and diagnostic utility. These few include the extracellular matrix-associated antigens tenascin and GP 240, defined by the monoclonal antibodies 81C6 and Mel-14, both of which are now in Phase I clinical trials, and membrane-associated ganglioside molecules, primarily 3', 6'-isoLD1, defined by the antibody DMAb-22. Recent identification of the overexpression of a deletion variant of the epidermal growth factor receptor (EGFRvIII) in up to 50% of the more malignant glial tumors and the subsequent creation of monoclonal antibodies that are specific to this molecule and do not recognize the wild-type EGFR provide the most exciting development yet in the design of specific antiglioma immunoconjugates. In addition, the tumor-specific nature of EGFRvIII combined with improved knowledge of immune mechanisms, especially in the context of the central nervous system, will facilitate the design of highly selective cell-mediated therapeutic approaches with a view toward obtaining tumor-specific immunity.

Animals↗