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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunotoxins (ITs) consist of cell-reactive ligands coupled to toxins or their toxic subunits. The ligands are usually antibodies, hormones, or growth factors and the toxins are of bacterial or plant origin. In the case of the plant toxin, ricin, its structure consists of a ribosome-inactivating A chain of 32 Kd linked by a disulfide bond to a galactose-specific lectin (B chain) of approximately 30 Kd. The A and B chains of ricin can be separated following reduction and the A chain can then be purified and chemically linked to different ligands to generate a cell-reactive conjugate. Studies using A chain-containing ITs to specifically delete tumor cells, or regulatory cells of the immune system began a decade ago. Initial in vitro experiments were successful and led to further experiments in vivo. However, in vivo studies carried out over the past five years in both animals and humans have demonstrated that the efficacy of ITs or conjugates in vivo is often poor due to problems involving instability of the conjugate, inferior potency, inaccessibility of tumor cells, nonspecific binding to cells other than the target cells, and the survival of antigen-negative mutants. In addition, immune responses against both the ligand and the A chain are usually elicited, precluding repeated therapy. During the past several years, there have been attempts to solve these problems and thereby develop more effective ITs. By analogy with conventional chemotherapeutic agents, it could be predicted that immunotoxins will require many years of study to optimize their construction and therapeutic regimens.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The development of immunotoxins for the therapy of cancer, AIDS, and immune dysfunctions. 307 26

By altering the receptor binding specificity of the highly potent natural toxin ricin, a macrophage specific immunotoxin was developed. Ricin ordinarily does not demonstrate cell type specificity and is capable of binding and entering cells through galactose containing receptors resulting in rapid cell death. A murine anti-rat peritoneal macrophage IgGl monoclonal antibody, B-6, was developed to serve as a target specific carrier for ricin. By covalently binding monoclonal antibody B-6 and reversibly binding lactose to ricin, a new biologically active hybrid toxin possessing macrophage specificity was developed. When P3X63-Ag8.653 myeloma cells, which served as an nonspecific target cell type, and macrophages were treated with the ricin conjugate over a broad range of concentrations and various time periods, the conjugate demonstrated substantially greater toxicity toward macrophages than myeloma cells even though both cell types responded similarly to treatments with unconjugated ricin. It was also observed that ricin was considerably more toxic to macrophages when conjugated to monoclonal antibody B-6 than unconjugated ricin. Through ricin-antibody conjugation a high degree of specificity and toxicity can be attained potentially suitable for anti-tumor reagents and immuno-modulators.
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PMID:Target ricin by coupling to an anti-macrophage monoclonal antibody. 308 61

The blood clearance and tissue distribution of immunotoxins composed of either intact or Fab' fragments of tumor-reactive, monoclonal rat antimurine immunoglobulin D (anti-delta) or nonreactive, normal rat immunoglobulin G and ricin A chain (native or chemically deglycosylated) were determined in BCL1 tumor-bearing mice. In the presence of accessible target cells, neither the valency of the antibody nor deglycosylation of the A chain affect the initial rate of clearance (alpha phase) of immunotoxins from the blood; however, both factors affect the levels of tumor-specific and nonspecific localization of the immunotoxins. Thus, the use of immunotoxins with deglycosylated A chain greatly reduced the levels of nonspecific uptake by the liver and concomitantly increased tumor-specific localization. Immunotoxins prepared with Fab' fragments of anti-delta antibody and deglycosylated A chain were twice as effective at localizing to splenic tumor than immunotoxins prepared with intact immunoglobulin G and deglycosylated A chain. Approximately 90% of tumor-specific localization of anti-delta immunotoxins occurred within 1 h after injection and less than 5% of the immunotoxin remained in the circulation 4 h after injection. In addition, the antigen-binding capacity of the remaining circulating immunotoxins decreased in a linear manner over the first 10 h to approximately 20% of the initial binding activity. Thus, by 10 h after injection, only 2-3% of injected immunotoxin remained in the circulation and this material expressed little antigen reactivity. Analysis of the in vivo stability of circulating 125I-labeled immunotoxins in tumor-bearing mice demonstrated that Fab' immunotoxins are more stable than IgG immunotoxins prepared with N-succinimidyl-3-(2-pyridylthio)propionate. In BCL1-bearing mice, significant splitting of the anti-delta immunotoxins did not occur until tumor localization was virtually complete.
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PMID:Pharmacokinetics of tumor-reactive immunotoxins in tumor-bearing mice: effect of antibody valency and deglycosylation of the ricin A chain on clearance and tumor localization. 325 46

The in vivo therapeutic effects of Fab' and IgG anti-delta (anti-IgD)-ricin A chain immunotoxins were compared in mice bearing the surface IgD-positive BCL1 leukemia. The immunotoxins were prepared with either native or deglycosylated ricin A chain. Immunotoxin therapy was assessed both by the number of cells bearing the BCL1 immunoglobulin idiotype which remained in the spleen 24-48 h after injection with immunotoxin and by adoptive transfer of these spleen cells into normal mice. Immunotoxins prepared with either Fab'-anti-delta or IgG-anti-delta and native A chain induced a dose-dependent reduction in the number of idiotype-positive BCL1 cells present in the spleens of the tumor-bearing mice. The maximal therapeutic response was achieved with 250 micrograms of immunotoxin (containing 80-100 micrograms A chain) per mouse for both immunotoxins, resulting in tumor reduction of approximately 90%. This represents an elimination of 3-4 X 10(8) tumor cells. Reduction in the number of tumor cells was not observed with control reagents including antibody alone, antibody mixed with A chain, or an immunotoxin of irrelevant specificity. A Fab' immunotoxin prepared with deglycosylated ricin A chain was approximately 5-fold more effective as an antitumor reagent than the same immunotoxin prepared with native A chain; thus, optimal therapy was achieved after injection of 50 micrograms of immunotoxin (containing 15-20 micrograms A chain). Since the immunotoxins prepared with deglycosylated A chain were only 2-3-fold more toxic to the mice than those prepared with native A chain, the former resulted in a 2-3-fold increase in the therapeutic index.
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PMID:In vivo therapy of the BCL1 tumor: effect of immunotoxin valency and deglycosylation of the ricin A chain. 325 47

Immunotoxins comprise a new class of cell-type specific cytotoxic reagents which consist of a monoclonal antibody linked to a protein toxin. This report examines the efficacy of intrathecal immunotoxin therapy for the treatment of tumors of the cerebrospinal fluid compartment. A syngeneic animal model of leptomeningeal neoplasia was developed in which percutaneous inoculation of L2C tumor cells into the cisterna magna of Strain 2 guinea pigs produced disseminated leptomeningeal and intraventricular leukemia and death. Percutaneous intracisternal injection of 2 micrograms of an anti-idiotype monoclonal antibody (M6)-intact ricin immunotoxin 24 hours following intracisternal inoculation of 10(5) L2C cells (10,000 times the lethal dose) produced prolonged survival (p less than 0.005) of tumor-bearing animals. The immunotoxin therapy caused no detectable toxicity. Intracisternal injection of either M6 monoclonal antibody alone or a nonspecific control immunotoxin had no therapeutic effect. The observed extension of survival times in immunotoxin-treated animals corresponds to a median 2- to 3-log (99% to 99.9%) and, in some animals, possibly a 5-log (99.999%) or greater kill of tumor cells. These results support a possible role for immunotoxins in the clinical treatment of central nervous system neoplastic disease involving compartments (intrathecal, intraventricular, or cystic tumor).
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PMID:Efficacy of intrathecal immunotoxin therapy in an animal model of leptomeningeal neoplasia. 325 32

We developed a model to assess the therapeutic effects of the 45-2D9-ricin A-chain immunotoxin (RTA) on pulmonary metastases. The 45-2D9 mouse monoclonal antibody recognizes a Mr 74,000 glycoprotein highly expressed by rat fibroblasts transformed with the Kirsten sarcoma virus (transformed rat fibroblasts). These cells metastasize spontaneously and form lung colonies in nu/nu and irradiated BALB/c mice. Injection i.v. of 45-2D9-RTA specifically reduced formation of spontaneous pulmonary metastases and lung colonies originating from freshly disaggregated tumor cells or cultured cells. Antibody alone or mixed with unconjugated ricin A chain and an immunotoxin that recognizes a melanoma-associated antigen were ineffective. Unconjugated 45-2D9 antibody specifically blocked the 45-2D9-RTA activity in vivo. Administration of the lysosomotrophic agents ammonium chloride and chloroquine in vivo did not potentiate immunotoxin-mediated reduction in lung colonies although they were effective in vitro. Monensin potentiated 45-2D9-RTA activity in vitro and in vivo.
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PMID:Mediation of reduction of spontaneous and experimental pulmonary metastases by ricin A-chain immunotoxin 45-2D9-RTA with potentiation by systemic monensin in mice. 325 69

The use of tumor immunotherapy using whole ricin-antibody conjugates is complicated by the nonspecific lectin activity of the ricin B-chain which leads to toxic side effects. A novel method of coupling whole intact ricin to monoclonal antibody (MoAb) is described herein, where the nonspecific binding of the ricin B-chain is blocked. The coupling was done using the bifunctional reagents S-acetylmercaptosuccinic anhydride for antibody and succinimidyl 3-(2-pyridyldithio)propionate for ricin, and this resulted in the loss of B-chain binding activity, while impairing neither the toxic potential of the A-chain nor the activity of the MoAb. The purified immunotoxins could not bind to lactose-Sepharose and were equally cytotoxic in vitro to MoAb-reactive cell lines in the presence or absence of lactose. The coupling method was suitable for six different ricin-antibody conjugates and also using ricin deglycosylated by treatment with periodate. However, the blocking of the ricin B-chain was only effective with whole IgG molecules as F(ab')2-ricin immunotoxins could, like ricin, bind to lactose-Sepharose. Ricin-antibody conjugates reduced the [3H]leucine incorporation of appropriate target cells by 50% at a concentration of 6 to 45 ng/ml, whereas nonreactive antibody immunotoxins were not toxic to the target cells at concentrations as high as 10(4) ng/ml. The specific cytotoxicity of these immunotoxins could be inhibited by the addition of unconjugated reactive MoAb; the presence of lactose or a nonreactive MoAb did not significantly affect the observed cytotoxicity. Thus, whole ricin-antibody conjugates produced in this way do not bind nonspecifically to target cells, the most important implication being that such immunotoxins should be more potent that ricin A-chain conjugates and capable of being used in vivo.
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PMID:Novel synthesis and in vitro characterization of disulfide-linked ricin-monoclonal antibody conjugates devoid of galactose binding activity. 326 Aug 14

An immunotoxin prepared with the pan-T-cell, anti-CD5, antibody T101, and purified ricin A-chain (RTA) was selectively cytotoxic in vitro, inactivating protein synthesis in the human T-cell line MOLT-4 but not in the human B-cell line 8392. Modulation studies showed that the immunoconjugate was more rapidly cleared from the cell surface than unconjugated T101. Preclinical evaluation of T101-RTA was conducted in a human T-cell, athymic mouse model (Dillman et al., Cancer Res., 45:5632-5336, 1985). Tumor-bearing mice received single i.p. injections of saline, T101, UPC-10 (irrelevant IgG2a), unconjugated RTA, an irrelevant conjugate, UPC-10-RTA, a mixture of T101 plus RTA, or T101-RTA. T101-RTA was the most effective reagent. Thirty animals given injections of 33 micrograms of T101 showed reductions in tumor growth (compared to tumor growth in animals receiving phosphate-buffered saline) but no complete regressions. No decrease in tumor growth was observed with UPC-10. Animals given 12 micrograms of free RTA exhibited reduced tumor growth but only one complete regression was observed; similar results were obtained with mice given 45 micrograms of UPC-10-RTA or a mixture of 33 micrograms of T101 plus 12 micrograms of RTA. Eleven complete regressions and 18 partial regressions were produced in the 46 animals given injections of 45 micrograms of T101-RTA and tumor growth was almost completely blocked. No toxicity was observed in any experimental arm. These results suggest that T101-RTA may be administered safely and with significant antitumor effect.
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PMID:Inhibition of human T-cell tumor growth by T101-ricin A-chain in an athymic mouse model. 326 27

Four mouse monoclonal antibodies (mAb) (8C, IgG2a; M2A, IgG2a; M2D, IgG2b; 10B, IgG1) directed against the human ovarian adenocarcinoma cell line HEY were compared for their ability in the free form and as immunotoxins made with recombinant ricin A chain (rRA) to inhibit the growth of HEY cells. For in vitro studies cultured HEY cells were assayed for protein synthesis and plated in agarose to form colonies, and for in vivo studies they were injected intraperitoneally (i.p.) into BALB/c nu/nu (nude) mice at a challenge dose (3 X 10(5) cells) which produced carcinomatosis with ascites, leading to death 30 days following injection. In the free form, mAB 8C was the most potent in inhibiting colony formation in the complement (C)-mediated and ADCC (antibody-dependent cell-mediated cytoxicity) assays in vitro. This mAb was also the only one capable of prolonging survival of mice, both in tumor cell neutralization, and tumor growth inhibition experiments. The four mAb-rRA immunotoxins were effective in inhibiting protein synthesis in vitro in the presence of 10(-7) M monensin. However, in vivo, only 8C-rRA and M2A-rRA were capable of prolonging survival of mice in tumor growth inhibition experiments. Our results suggest that mAb 8C might be useful in the free form and as an 8C-rRA immunotoxin for i.p. immunotherapy of ovarian cancer.
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PMID:Comparison of growth inhibition of a human ovarian adenocarcinoma cell line by free monoclonal antibodies and their corresponding antibody-recombinant ricin A chain immunotoxins. 326 79

A monoclonal anti-Thy-1.1 antibody (OX7) was coupled to either native or chemically deglycosylated ricin A-chain (dgA) using one of two different cross-linking agents. One cross-linker, N-succinimidyloxycarbonyl-alpha-methyl-alpha-(2-pyridyldithio)tolu ene (SMPT), generates a sterically hindered disulfide bond which is relatively resistant to reduction, whereas the other, 2-iminothiolane hydrochloride, generates an unhindered disulfide bond with greater lability. A two-compartment pharmacokinetic model was used to analyze the blood levels of each immunotoxin and its breakdown product (free antibody) after i.v. injection into mice. Immunotoxins prepared with SMPT broke down in vivo 6.3-fold more slowly than those prepared with 2-iminothiolane hydrochloride, and immunotoxins containing native A-chain were cleared 2- to 3-fold more rapidly from the bloodstream than those containing dgA. As a result, 24 h after injection, 16% of the OX7-SMPT-dgA remained in the blood as compared with 0.4 to 2.5% of the other immunotoxins. Immunotoxins prepared with dgA were about 3-fold more toxic to mice than those prepared with native A-chain, whereas immunotoxins prepared with SMPT were only slightly more toxic than those prepared with 2-iminothiolane hydrochloride. When equivalent toxic doses of the immunotoxins were administered i.v. to mice which had been given injections of Thy-1.1+ AKR-A/2 lymphoma cells, the OX7-SMPT-dgA gave the best antitumor effect. A dose equivalent to one-seventh of the median lethal dose extended the survival time of the animals by the extent expected if 99.999% of the tumor cells had been eradicated. Furthermore, the tumors that did develop in the mice treated with OX7-SMPT-dgA were mutants which were resistant to all the immunotoxins. Some of the mutants were deficient in Thy-1.1 whereas others were not. In conclusion, both the use of the SMPT cross-linker and deglycosylation of the A-chain significantly improve the therapeutic index of the immunotoxins in AKR-A/2 tumor-bearing mice.
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PMID:Improved antitumor effects of immunotoxins prepared with deglycosylated ricin A-chain and hindered disulfide linkages. 326 86


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