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PubMed2004

Cell death triggered by alpha-emitting 213Bi-immunoconjugates in HSC45-M2 gastric cancer cells is different from apoptotic cell death.

PURPOSE: Radioimmunotherapy with alpha-particle-emitting nuclides, such as 213Bi, is a promising concept for the elimination of small tumour nodules or single disseminated tumour cells. The aim of this study was to investigate cellular damage and the mode of cell death triggered by 213Bi-immunoconjugates. METHODS: Human gastric cancer cells (HSC45-M2) expressing d9-E-cadherin were incubated with different levels of activity of 213Bi-d9MAb targeting d9-E-cadherin and 213Bi-d8MAb, which does not bind to d9-E-cadherin. Micronucleated (M) cells, abnormal (A) cells and apoptotic (A) [(MAA)] cells were scored microscopically in the MAA assay following fluorescent staining of nuclei and cytoplasm. Chromosomal aberrations were analysed microscopically following Giemsa staining. The effect of z-VAD-fmk, known to inhibit apoptosis, on the prevention of cell death was investigated following treatment of HSC45-M2 cells with sorbitol as well as 213Bi-d9MAb. Activation of caspase 3 after incubation of HSC45-M2 cells with both sorbitol and 213Bi-d9MAb was analysed via Western blotting. RESULTS: Following incubation of HSC45-M2 human gastric cancer cells expressing d9-E-cadherin with 213Bi-d9MAb the number of cells killed increased proportional to the applied activity concentration. Microscopically visible effects of alpha-irradiation of HSC45-M2 cells were formation of micronuclei and severe chromosomal aberrations. Preferential induction of these lesions with specific 213Bi-d9MAb compared with unspecific 213Bi-d8MAb (not targeting d9-E-cadherin) was not observed if the number of floating, i.e. unbound 213Bi-immunoconjugates per cell exceeded 2 x 10(4), most likely due to intense crossfire. In contrast to sorbitol-induced cell death, cell death triggered by 213Bi-immunoconjugates was independent of caspase 3 activation and could not be inhibited by z-VAD-fmk, known to suppress the apoptotic pathway. CONCLUSION: 213Bi-immunoconjugates seem to induce a mode of cell death different from apoptosis in HSC45-M2 cells.

Alpha Particles↗
PubMed2003

Monoclonal antibody drug immunoconjugates for targeted treatment of cancer.

Monoclonal antibodies (mAb) directed to tumor-associated antigens (TAA) or antigens differentially expressed on the tumor vasculature have been covalently linked to drugs that have different mechanisms of action and various levels of potency. The use of these mAb immunoconjugates to selectively deliver drugs to tumors has the potential to both improve antitumor efficacy and reduce the systemic toxicity of therapy. Several immunoconjugates, particularly those that incorporate internalizing antibodies and tumor-selective linkers, have demonstrated impressive activity in preclinical models. Immunoconjugates that deliver doxorubicin, maytansine and calicheamicin are currently being evaluated in clinical trials. The feasibility of using immunoconjugates as cancer therapeutics has been clearly demonstrated. Gemtuzumab ozogamicin, a calicheamicin conjugate that targets CD33, has recently been approved by the Food and Drug Administration (FDA) for treatment of acute myelogenous leukemia (AML). This review concentrates on the properties of the tumor and the characteristics of the mAb, linker, and drugs that influence the efficacy, potency, and selectivity of immunconjugates selected for cancer treatment.

Aminoglycosides↗
PubMed1993

Efficacy of anti-CD5 F(ab')2 and Fab' immunoconjugates in human peripheral blood lymphocyte-reconstituted severe combined immunodeficient mice.

A human peripheral blood lymphocyte-reconstituted severe combined immunodeficient (hu-PBL-SCID) mouse model was used to compare in vivo efficacy of immunoconjugates directed against the CD5 antigen present on human T-cells. Four anti-CD5 immunoconjugates were tested, composed of chimeric human-mouse (cH65) F(ab')2 or Fab' fragments chemically linked to recombinant gelonin (rGEL) or the 30,000 M(r) glycoform of ricin A chain (RTA30). Immunoconjugate treatment was initiated approximately 3 weeks after PBL transplantation and consisted of five consecutive daily bolus i.v. injections. Efficacy was subsequently assessed by quantitation of human T-cells in spleens, blood and peritoneal lavage fluid using 3-color flow cytometry. cH65 F(ab')2- and cH65 Fab'-rGEL conjugates were essentially equally effective at depleting human T-cells from SCID mouse tissues, suggesting that bivalent binding is not required for efficacy when rGEL is the cytotoxic moiety. Treatment with unconjugated F(ab')2, unconjugated Fab' or a Fab-rGEL immunoconjugate of irrelevant binding specificity did not result in a significant depletion of T-cells, demonstrating that the cytotoxic moiety and a relevant human T-cell binding moiety are both required for efficacy. In contrast to the results observed with the rGEL conjugates, cH65 Fab'-RTA30 was not as effective as cH65 F(ab')2-RTA30 in depleting human T-cells from SCID mouse tissues. This paralleled in vitro findings in a human PBMC cytotoxicity assay, which demonstrated that cH65 Fab'-RTA30 was 17-fold less potent than cH65 F(ab')2-RTA30 and approximately 50-fold less potent than the rGEL conjugates.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

A membrane-lytic immunoconjugate selective for human tumor T-lymphocytes.

An immunoconjugate was constructed from a monoclonal antibody recognizing human T-lymphoblastoid cells and a membrane-lytic cytotoxin purified from the venom of the Thailand cobra. Activities of this novel immunoconjugate were compared using human and murine T-lymphocyte cell lines. The ability of the conjugate to inhibit human T-cell proliferation, as measured by incorporation of [3H]thymidine, was three to four times higher than its ability to inhibit proliferation of mouse L1210 cells. The immunoconjugate EC50 for human CEM cells was equivalent to 0.1 nmoles per 2 x 10(5) target cells. Immunoconjugate selectivity paralleled the monoclonal antibody's binding characteristics. Preincubation with free antibody blocked the effect of the conjugate, but only upon the human target cells. This study supports the feasibility of directing a toxic moiety to the surface of a cancer cell to accomplish cell destruction without requiring prior toxin internalization and uncoupling from its antibody carrier.

Animals↗
PubMed1991

Immunohistochemical and pharmacokinetic characterization of site-specific immunoconjugate 15A8-glycyl-tyrosyl-(N-epsilon-diethylenetriamine pentaacetic acid)-lysine derived from anti-breast carcinoma monoclonal antibody 15A8.

In this study, the breast carcinoma-reactive monoclonal antibody 15A8 and a site-specific immunoconjugate of the antibody, 15A8-glycyl-tyrosyl-(N-epsilon-diethylenetriamine pentaacetic acid)-lysine (15A8-GYK-DTPA), were characterized by immunohistological methods for reactivity with normal and neoplastic human tissues and normal cynomolgus monkey tissues. In addition, 15A8-GYK-DTPA labeled with 111In was assessed by in vivo imaging and pharmacokinetic studies for localization to human tumor xenografts in nude mice. The native antibody and the site-specific immunoconjugate exhibited similar limited reactivity with normal human tissues. Specifically, epithelial structures, including normal breast epithelium, lung alveoli, bronchial epithelium and glands, liver bile ducts, pancreatic ducts, kidney distal and collecting tubules, epidermal and esophageal epithelium, endometrial glands, and thymic Hassall's corpuscles, were reactive. Normal monkey tissues stained with 15A8 exhibited a similar pattern of reactivities. Antibody 15A8 reacted broadly with epithelium-derived tumors; more than 60% of the cells in all of the breast, colon, non-small cell lung, ovarian, prostate, bladder, and renal carcinomas tested expressed the antigen. In contrast, a variety of nonepithelial neoplasms, including lymphomas, melanomas, sarcomas, and small cell lung carcinomas, were nonreactive. 15A8-GYK-DTPA-111In administered i.v. rapidly localized to and imaged both MX-1 and MCF-7 human breast carcinoma xenografts in nude mice, reaching maximal levels of about 20% of injected dose/g of tumor within 4 days. No unusual localization to any nontumor tissue or organ was seen; the level of radioactivity in the normal tissues and organs was at or below that seen in the blood. Furthermore, the immunoconjugate did not accumulate in xenografts of the antigen-negative breast carcinoma ZR-75-1, which indicates that tumor localization was antigen specific. Pharmacokinetic studies in cynomolgus monkeys suggested that significant amounts of 15A8-GYK-DTPA-111In did not localize to normal epithelia and demonstrated that the immunoconjugate was not toxic. These findings suggest that antibody 15A8 may be useful in the diagnosis and therapy of breast cancer and possibly other carcinomas.

Animals↗
PubMed1991

Enhanced tumor uptake of macromolecules induced by a novel vasoactive interleukin 2 immunoconjugate.

Low uptake of monoclonal antibodies (MAbs) in cancer lesions is a significant problem in cancer therapy. Recent studies have shown that antibody uptake in tumor is controlled in large part by the tumor blood flow and the vascular permeability of the tumor endothelium. We have hypothesized that these physiological properties of tumor vessels may be altered by pretreatment with vasoactive drugs or peptides linked to tumor-specific MAbs. To test this hypothesis, two MAbs, Lym-1 directed against human malignant lymphomas and B72.3 reactive with the TAG-72 antigen expressed in solid tumors, were chemically conjugated with human recombinant interleukin 2 (IL-2). IL-2 has been used in humans to activate lymphokine-activated killer cells for the treatment of cancer but is also known to produce a generalized vascular permeability by an unknown mechanism when used systemically. Chemical conjugation of IL-2 to MAbs appears to destroy its cytokine function as shown by T-cell proliferation studies in vitro. Despite this finding, MAb/IL-2 immunoconjugates retain their ability to produce an enhanced vascular permeability when injected i.v. into nude mice bearing relevant tumor models only. Biodistribution studies using 125I-labeled tracer Lym-1 have demonstrated that the Lym-1/IL-2 immunoconjugate can increase antibody uptake in tumor by a factor of 4 in a time (2.5-h pretreatment)- and dose (30 micrograms/mouse)-dependent manner. In contrast, treatment of mice with free IL-2 and antibody showed this effect in all organs of the mouse including the tumor. Bidirectional crossover imaging studies in individual tumor-bearing nude mice showed improved uptake and decreased blood pool when the MAb/IL-2 immunoconjugates were used compared to controls. Finally, tumor blood flow and vascular permeability studies demonstrate that the physiological effect of the MAb/IL-2 is due to a reversible and specific vascular leakage at the tumor site. These studies indicate that pretreatment with this novel immunoconjugate may enhance the diagnostic and therapeutic potential of MAbs, drugs, and other macromolecules for the treatment of cancer.

Animals↗
PubMed1990

Application of target-specific drug immunoconjugates to experimental bone marrow replacement therapy in mice.

Immunoconjugates whose cytotoxic component consists of a phytopeptide are often used as purging agents in bone marrow replacement therapy. Less popular are drug immunoconjugates containing a small molecular weight cytotoxic drug attached to the target-specific conjugand via an appropriate spacer molecule. High target specificity, resistance of the drug to intralysosomal proteases and, once cleaved from the spacer, ready exist of the drug from the lysosome are among the advantages drug immunoconjugates hold over phytotoxin immunoconjugates. The cytotoxic drug daunomycin attached via an acid-sensitive spacer to monoclonal antibody of appropriate specificity was shown to purge murine bone marrow of contaminating tumor cells without affecting its hematopoietic potential. Lethally irradiated mice reconstituted with syngeneic bone marrow from which contaminating lymphoma cells had been removed survived indefinitely. Furthermore, lymphoma-bearing mice, provided they were sufficiently irradiated to eliminate tumor cells in situ, were successfully reconstituted with fully allogeneic bone marrow from which potentially graft-versus-host-reactive T-cells had been purged.

Animals↗
PubMedDate not supplied

Anti-tumor activity of CC49-doxorubicin immunoconjugates.

The TAG72 reactive monoclonal antibody CC49 was conjugated to doxorubicin with a malonate linker. The immunoconjugate, designated CC49-BAMME-CH-DOX, was approximately a log less potent than unconjugated doxorubicin in an in vitro cytotoxicity assay. Immunoreactivity of the antibody was fully retained. When evaluated in a nude mouse xenograft model with the antigen positive LS174T human colorectal tumor target, CC49-BAMME-CH-DOX and free doxorubicin had similar tumor suppressive activities. The immunoconjugate was clearly less toxic, however, as measured by weight loss and deaths. When evaluated in an NIH:OVCAR-3 human ovarian carcinoma xenograft model, CC49-BAMME-CH-DOX was superior at prolonging survival in comparison to free doxorubicin, unmodified CC49, and a non tumor binding doxorubicin immunoconjugate. These results indicate that targeting of doxorubicin with the CC49 antibody can improve the toxicity and/or the potency of the drug, depending on the tumor target being evaluated. CC49-Doxorubicin immunoconjugates should be considered for clinical evaluation.

Animals↗
PubMed1996

[Preparation and in vitro activity of monoclonal antibody-pharmorubicin immunoconjugates].

Bifunctional agent adipic dihydrate was used to form hydrazon bond between polyglutamic acid (PGA) and pharmorubicin (PAR). Under controlled condition, a relatively high rate of conjugation was obtained with no self-condensation. The value of PGA/PAR was in positive portion with the molecular weight (MW) of PGA: per 8-11 glutamic acid monomer linking one pharmorubicin. When PGA of MW 14,300 was used as carrier, the ratio of PGA/PAR was 1:11. After conjugating with anti-hepatoma monoclonal antiboty (McAb), an immunoconjugate of McAb:PGA:PAR being 1:2:22 was obtained. The immunoconjugate retained the binding activity to targeted cell compared with the purified and the oxidized antibody. Pharmacological studies in vitro showed lower cytotoxicity of the immunoconjugate than the free drug, but selective cytotoxicity directed by antibody was observed. Consequently, the immunoconjugate McAb-PGA-PAR with high ratio of drug/McAb as well as moderate targeting cytotoxity in vitro was successfully prepared. That makes it possible for the preparation of cell-targeted drug which is expected to be benificial to tumor treatment.

Antibodies, Monoclonal↗
PubMed1994

In vitro activity of immunoconjugates between cisplatin and an anti-CA125 monoclonal antibody on ovarian cancer cell lines.

Cis-diammine dichloro platinum (II) (CDDP), is a highly potent antineoplastic agent that is used in the treatment of ovarian cancer. However, the clinical use of CDDP is restricted by its severe side effects. In order to reduce these side effects and to enhance its therapeutic efficacy, we developed specific immunoconjugates consisting of the murine monoclonal antibody OC125 and CDDP, using diethylene triamine pentaacetic acid (DTPA) as a linker. The coupling efficiencies of the different preparations synthesized, varied between 1.10 +/- 0.42 and 2.65 +/- 1.60 mol of CDDP per mol of antibody protein. Despite the chemical modification of the antibody molecule, specific binding activity of the OC125-CDDP conjugates toward the CA125 antigen was maintained as was demonstrated by means of immunohisto-/cytochemical staining of frozen sections of ovarian cancer tissue, amniotic epithelium, and the CA125 positive ovarian cancer cell line NIH:OVCAR 3. The antiproliferative activity of the immunoconjugates was tested against the human ovarian cancer cell lines NIH:OVCAR 3 and SKOV 3, applying a kinetic crystal violet microassay. Despite the promising results obtained with the specific immunostaining of the target cells, no significant antiproliferative activity of our immunoconjugates against the cell lines tested was observed. One possible explanation for the lack of antitumor activity could be the fact that CA125 is released in large amounts by the NIH:OVCAR 3 cells. This may have prevented an efficient immunotargeting of the cancer cells by the formation of soluble immune complexes.

Antibodies, Monoclonal↗
PubMed2006

Enhanced fluorescence resonance energy transfer immunoassay with improved sensitivity based on the Fab'-based immunoconjugates.

Fluorescence resonance energy transfer (FRET) is a powerful technique to monitor protein-protein interaction. Recently, we developed homogeneous and noncompetitive immunoassay based on the enhanced FRET by leucine zipper interaction. Here we improved the assay by establishing a general method for preparation of the Fab'-based immunoconjugate. Anti-human serum albumin Fab' numbers 11 and 13 were chemically conjugated with recombinant proteins consisting of thioredoxin, flexible linker, and green fluorescent protein color variant tethered with a leucine zipper motif. Compared with single chain antibody variable region-based fusion proteins prepared by the gene fusion method in our previous study, the resultant Fab'-based immunoconjugates accomplished an assay with nearly 10 times greater sensitivity. Furthermore, the conjugation method enabled us to apply the assay generally to measurement of another high-molecular weight antigen for which antibodies prepared for sandwich immunoassay are commercially available. Because of the facility and generality of the preparation method for the immunoconjugate, the assay is expected to be applied to many antigens that require rapid diagnosis and moderate measurement range.

Fluorescence Resonance Energy Transfer↗
PubMed1996

Treatment of ovarian cancer with photodynamic therapy and immunoconjugates in a murine ovarian cancer model.

In photodynamic therapy (PDT), photosensitisers accumulate somewhat preferentially in malignant tissues; photoactivation with appropriate wavelength of light release toxic molecular species which lead to tumour tissue death. In order to target ovarian cancer with increased specificity, a chlorin-based photosensitiser (chlorin e6 monoethylendiamine monoamide) was conjugated to OC125, a monoclonal antibody recognising an antigen expressed in 80% of non-mucinous ovarian cancers. In previous work, this immunoconjugate (IC) was shown to be selectively phototoxic to cancer cells from ovarian cancer patients ex vivo and to localise preferentially in ovarian cancer tissue in vivo. In this study we report results from in vivo phototoxicology and photodynamic treatment studies using this IC in a murine model for ovarian cancer. A comparison of single vs multiple treatments was also made. For in vivo experimentation, Balb C nude mice were injected with 30 x 10(6) NIH:OVCAR 3 cancer cells to create an ascitic tumour model. Animals were then given intraperitoneal injections of the immunoconjugate (0.5 mg kg-1). Twenty-four hours later the intraperitoneal surfaces were exposed to 656 nm light from an argon-ion pumped-dye laser (50 mW, 656 nm), using a cylindrical diffusing tip fibre. The overall treatment was given either once or multiply. No animals died from treatment complications. Twenty-four hours following one and three PDT treatments, the percentage of viable tumour cells in the ascites of the treated animals analysed ex vivo was 34% and 5% of control for one and three treatments respectively. With respect to survival, all control mice (n = 18) died between 30 and 50 days. However, for those treated three times (n = 10), 40% were still alive after 50 days, and for those treated four times (n = 12) 58% were alive after 50 days. Evaluation with log-rank test revealed a significant survival with intraperitoneal PDT compared with controls (P = 0.0006). These preliminary results suggest that PDT with an OC125 immunoconjugate may be an effective therapy for the management of advanced ovarian cancer. Clinical application of this therapy needs to be further optimised and may require multiple treatments, similar to fractionated radiation therapy and cyclic chemotherapy, in order to control malignant disease with acceptable toxicity to normal tissue.

Animals↗
PubMed2000

Active drug targeting with immunoconjugates to choroidal neovascularization.

PURPOSE: Active drug targeting with monoclonal antibody to neovascular vessels may be a potential treatment for choroidal neovascularization (CNV) in age-related macular degeneration (AMD). Endoglin (CD105) is a proliferating endothelial cell marker with excellent potential for targeting. The goals of this study were to investigate the expression of CD105 in CNV membranes surgically excised from patients with AMD and CNV lesions induced by intense laser photocoagulation in a cynomolgus monkey and to evaluate the in vitro effect of immunoconjugates on endothelial cells. METHODS: CNV membranes were surgically excised from 10 patients with AMD. Experimental CNV was induced by intense laser photocoagulation in a cynomolgus monkey. Immunolocalization of CD105 on frozen sections of CNV lesions was studied by immunohistochemical evaluation. Anti-von Willebrand's factor antibody was used as an endothelial cell marker. The cytotoxic effect of immunoconjugates of anti-CD105 monoclonal antibody and dextran binding mitomycin C on human umbilical vein endothelial cells (HUVECs) was evaluated in vitro. RESULTS: Endothelial cells demonstrated strong immunoreactivity of CD105 in all surgically excised CNV membranes. In the monkey eye, CD105-positive cells were detected only in CNV lesions but not in normal chorioretinal tissues. Immunoconjugates with anti-CD105 monoclonal antibody showed a specific inhibitory effect on proliferating HU-VECs. CONCLUSIONS: These results suggest that anti-CD105 monoclonal antibody-mediated drug targeting has a potential to treat CNV in AMD.

Aged↗
PubMed2002

Immunoconjugates: current status and future potential.

Whilst the concepts involved in immunoconjugates go back two centuries to the ideas of Ehrlich; it was only in the early 1980s that biotechnology gave us the tools to make pure immunoconjugates, in quantities sufficient for clinical studies [Garnett, M.C. (2002) "Targeted drug conjugates: principles and progress". Advanced Drug Delivery Reviews, 53, 171-216]. The early problems with immunogenicity that antibodies encountered in the clinic were addressed, in part by chimeric antibodies and later with humanised antibodies. At this time a number of different approaches were seriously evaluated for immunoconjugates, all with significant industrial backing, particularly from the emerging biotechnology companies.

Drug Delivery Systems↗
PubMed1995

Lysis of small cell carcinoma of the lung (SCCL) cells by cytokine-activated monocytes and natural killer cells in the presence of bispecific immunoconjugates containing a gastrin-releasing peptide (GRP) analog or a GRP antagonist.

Lung cancer remains the leading cause of cancer deaths in the United States. We have developed a new immunotherapeutic approach to the treatment of small cell carcinoma of the lung (SCCL) by targeting the gastrin-releasing peptide receptor (GRP-R) expressed on the surface of these cells. Bispecific immunoconjugates were constructed by chemical fusion of a GRP analog or a GRP antagonist with monoclonal antibodies directed to the cytotoxic trigger molecules Fc gamma RI and Fc gamma RIII on various immune effector cells. We demonstrated that these bispecific immunoconjugates bound to target SCCL cells in a dose-dependent manner. In the presence of these immunoconjugates, more than 80% of SCCL cells were lysed by cytokine-activated monocytes and natural killer (NK) cells measured by a 51Cr-release assay. These data indicate that bifunctional antibodies targeting GRP may have clinical use.

Antibodies, Bispecific↗
PubMed1998

Effect of gelonin immunoconjugate with monoclonal antibody MSN-1 to endometrial adenocarcinoma on antigen-producing tumor cells in vivo.

Missile therapy, which destroys cancer cells specifically, has been advocated as an effective modality for the treatment of carcinoma. We have developed an immunoconjugate consisting of the monoclonal antibody MSN-1 (IgM), which reacts strongly with endometrial adenocarcinomas, combined with a plant hemitoxin named gelonin via a disulfide bond using N-succinimidyl-3-(2-pyridyldithio) propionate and 2-iminothiolane, and examined its selective cytotoxicity in athymic mice. The reductions in resected weights of target tumor cells, at the local site of MSN-1-gelonin immunoconjugate treatment, were 96% with local administration and 75% with caudal vein administration, as compared with the untreated group. There was no weight loss in treated mice. Our results suggest that this MSN-1-gelonin immunoconjugate has potential clinical applications in the treatment of endometrial adenocarcinomas.

Adenocarcinoma↗
PubMed1999

Enhanced effects of monoclonal antibody carboplatin immunoconjugates uptake and anti-tumor effects with angiotensin II and tumor necrosis factor.

The most important factor influencing the use of monoclonal antibody immunoconjugates for cancer treatment is effectiveness of enhancement for tumor targeting. We call attention to the vasoactive agents angiotensin II (ATII) for selective increase in tumor blood flow and cytokine tumor necrosis factor (TNF) to improve the vascular permeability of the tumor. Tumor localization and biodistribution were investigated by nude mice transplanted human colon adenocarcinoma (LS-180) with radiolabeled carboplatin immunoconjugates. Tumor activity 48 h after administration of ATII and TNF was significantly higher than in the control group. However, nonspecific accumulation in normal organs was not observed. In vivo anti-tumor effects in animals with ATII and TNF was significantly stronger than in those given the same dose drug alone or immunoconjugates alone. These results indicate that ATII and TNF could be useful tools for induction of stronger inhibition of tumor growth without systemic toxicity.

Adenocarcinoma↗
PubMed2000

In vitro efficacy of recombinant diphtheria toxin-murine interleukin-4 immunoconjugate on mouse glioblastoma and neuroblastoma cell lines and the additive effect of radiation.

OBJECT: The prognosis for patients with primary malignant brain tumors is poor despite aggressive treatment, and tumor recurrence is common regardless of the chosen therapy. Although multimodal treatment does not provide a cure, it is necessary to determine which treatment modalities have the greatest cytotoxic effect and can potentially prolong survival. Immunotoxin therapy is a novel approach for the treatment of tumors, and it has been successfully used in the central nervous system. Because the interleukin (IL)-4 receptor is commonly expressed on brain tumor cells, the purpose of this study was to evaluate the cytotoxic effect of using a modified diphtheria toxin-murine IL-4 (DT390- mIL4) immunoconjugate for the treatment of murine brain tumor cell lines and to determine whether the addition of radiation therapy could potentiate the effect of this agent. METHODS: Spontaneous murine glioblastoma (SMA-560) and two neuroblastoma (Neuro-2a and NB41A3) cell lines were treated using DT390-mIL4 at different concentrations, and the anti-mouse IL-4 monoclonal antibody (11B11) was used for blocking its cytotoxicity. Other SMA-560 and Neuro-2a cell lines were treated using 500 cGy of radiation 3 hours before DT390-mIL4 treatment. Cytotoxity was evaluated using a trypan blue viability assay. The immunoconjugate exhibited a dose-dependent cytotoxic effect with 50% inhibitory concentration values of 0.56 x 10(-9) M in SMA-560, 1.28 x 10(-9) M in Neuro-2a, and 0.95 x (-10) M in NB41A3 cell lines. The cytotoxicity of DT390-mIL4 was specifically blocked by an excess of 11B11. Cytotoxicity was additive when the DT390-mIL4 at 10(-9) M immunoconjugate administration was followed by radiation therapy. CONCLUSIONS: These results indicate that the IL-4 receptor can be a target for diphtheria toxin fusion proteins and that radiation can potentiate the effects of DT390-mIL4. The development of multimodal approaches to treat malignant brain tumors with agents that have different mechanisms of action may be beneficial.

Animals↗