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At least 19 recordsLinked to original sources
PubMed1991

Blocked and non-blocked ricin immunotoxins against the CD4 antigen exhibit higher cytotoxic potency than a ricin A chain immunotoxin potentiated with ricin B chain or with a ricin B chain immunotoxin.

An immunotoxin consisting of ricin A chain linked to the monoclonal antibody M-T151, recognising the CD4 antigen, was weakly toxic to the human T-lymphoblastoid cell line CEM in tissue culture. The incorporation of [3H]leucine by CEM cells was inhibited by 50% at an M-T151--ricin-A-chain concentration (IC50) of 4.6 nM compared with an IC50 of 1.0 pM for ricin. In contrast, immunotoxins made by linking intact ricin to M-T151 in such a way that the galactose-binding sites of the B chain subunit were either blocked sterically by the antibody component or were left unblocked, were both powerfully cytotoxic with IC50 values of 20-30 pM. The addition of ricin B chain to CEM cells treated with M-T151--ricin-A-chain enhanced cytotoxicity by only eight-fold indicating that isolated B chain potentiated the action of the A chain less effectively than it did as an integral component of an intact ricin immunotoxin. Ricin B chain linked to goat anti-(mouse immunoglobulin) also potentiated weakly. Lactose completely inhibited the ability of isolated ricin B chain to potentiate the cytotoxicity of M-T151--ricin-A-chain and partially (3- to 4-fold) inhibited the cytotoxicity of the blocked and non-blocked ricin immunotoxins. Thus, in this system, the galactose-binding sites of the B chain contributed to cell killing regardless of whether isolated B chain was associated with the A chain immunotoxin or was present in blocked or non-blocked form as part of an intact ricin immunotoxin. The findings suggest that the blocked ricin immunotoxin may become unblocked after binding to the target antigen to re-expose the cryptic galactose-binding sites. However, the unblocking cannot be complete because the maximal inhibition of [3H]leucine incorporation by the blocked immunotoxin was only 80% compared with greater than 99% inhibition by the non-blocked immunotoxin.

Animals↗
PubMed1991

Comparative biochemical, cytotoxic and pharmacokinetic properties of immunotoxins made with native ricin A chain, ricin A1 chain and recombinant ricin A chain.

Immunotoxins were constructed by attaching native ricin A chain, ricin A1 chain and recombinant ricin A chain to the mouse monoclonal IgG2a antibody Fib75 by means of a disulphide linkage using the hetero-bifunctional cross-linker SPDP. The Fib75 immunotoxins were of similar composition and exerted identical cytotoxic effects against the EJ human bladder carcinoma cell line in tissue culture. All 3 immunotoxins broke down to the same extent upon incubation with glutathione in vitro. The clearance of the immunotoxins from the circulation of normal Wistar rats was determined following i.v. administration. The concentration of intact immunotoxin in serum samples taken at various intervals up to 48hr after injection was measured by a ricin A chain-specific ELISA. The Fib75 immunotoxin made with native ricin A chain was removed from the circulation most rapidly. Fib75-recombinant ricin A chain persisted in the circulation at a higher level than Fib75-ricin A1 chain. A higher proportion of the ricin A1 chain immunotoxin was lost from the bloodstream during the alpha-phase. The beta-phase half-lives of Fib75-recombinant ricin A chain and Fib75-ricin A1 chain were similar, consistent with the identical susceptibility of the immunotoxins to cleavage by glutathione. The presence of the complex-type oligosaccharide side-chain on the A1 chain may have accelerated the clearance of the A1 chain immunotoxin in relation to that of the immunotoxin made with the aglycosyl recombinant A chain.

Animals↗
PubMed1992

The specific cytotoxicity of immunoconjugates containing blocked ricin is dependent on the residual binding capacity of blocked ricin: evidence that the membrane binding and A-chain translocation activities of ricin cannot be separated.

Recently we have developed blocked ricin, a derivative of native ricin in which the galactose-binding sites of the B-chain are blocked by covalent modification with affinity ligands. This modification impedes the binding function of the B-chain, while sparing its ability to facilitate the entry of the toxic subunit of ricin, the A-chain, into the cytoplasm. Immunotoxins prepared with blocked ricin approach the cytotoxic potency of native ricin with antibody-dependent specificity. Here we report that the high cytotoxic potency of these immunoconjugates, which is attributed to the preserved translocation function of the ricin B-chain, is dependent on the minimal residual lectin activity of blocked ricin. Our findings support the notion that two functions of ricin, membrane binding and translocation, cannot be separated.

Antigen-Antibody Complex↗
PubMed1984

The role of binding ligand in toxic hybrid proteins: a comparison of EGF-ricin, EGF-ricin A-chain, and ricin.

To analyze the influence of ricin B-chain on the toxicity of hybrid-protein conjugates, the rate of cellular uptake of conjugates, and the rate at which ricin A-chain (RTA) is delivered to the cytoplasm, we have constructed toxic hybrid proteins consisting of epidermal growth factor (EGF) coupled in disulfide linkage either to ricin or to RTA. EGF-ricin is no more toxic on A431 cells than EGF-RTA. The two conjugates demonstrate similar kinetics of cellular uptake (defined as antibody irreversible toxicity). EGF-RTA and EGF-ricin, like ricin, required a 2-2 1/2 hour period at 37 degrees before the onset of protein synthesis inhibition occurred. Our results suggest that RTA determines the processes which carry it, either in conjugate or toxin, from the plasma membrane binding site to the cytoplasm following endocytosis, and the ricin B chain is not required for these processes.

Biological Transport↗
PubMed1987

The complete amino acid sequence of the B-chain of ricin E isolated from small-grain castor bean seeds. Ricin E is a gene recombination product of ricin D and Ricinus communis agglutinin.

The complete amino acid sequence of the B-chain of ricin E has been determined. The reduced and carboxymethylated B-chain was digested with trypsin, followed by separation and purification of the resulting peptides using reverse-phase HPLC. The amino acid sequence of each tryptic peptide was determined employing the DABITC/PITC double-coupling method. The B-chain of ricin E proved to consist of 262 amino acid residues. By comparing the amino acid sequence of the B-chain of ricin E with those of ricin D and of Ricinus communis agglutinin, it was found that the B-chain of ricin E was composed of the N-terminal half of ricin D and C-terminal half R. communis agglutinin. This result suggested that the gene recombination probably occurred at the center region of two B-chain genes of ricin D and R. communis agglutinin.

Amino Acid Sequence↗
PubMed1990

The influence of anti-(ricin toxin A chain) monoclonal antibodies on the pharmacokinetics of ricin toxin A chain and recombinant ricin A chain in mice.

Two monoclonal antibodies against ricin toxin A chain (RTA) have been examined for their effects on the blood survival and biodistribution of RTA and recombinant ricin A chain in mice. When admixed with the toxins at 1:1 molar ratios prior to intravenous injection, the antibodies prolonged blood survival and whole-body retention of both species of RTA, and this was due essentially to reduced renal clearance of the toxins. Immune complexes were identified by gel filtration chromatography and immune precipitation with anti-IgG antiserum in mixtures prior to injection and in the serum of mice injected with the mixtures. An irrelevant monoclonal antibody showed no complex formation, and no effect on biodistribution. These studies have shown that immune complexes formed between monoclonal antibodies and protein antigens of molecular mass up to at least 30 kDa survive in the circulation, rather than being cleared by the reticuloendothelial system. Such antibodies could be used to modulate the biodistribution of toxic molecules such as ribosome-inhibiting proteins like RTA. This might be exploited therapeutically, for example in the construction of bispecific antibodies against ribosomal inhibiting proteins and tumour-associated antigens.

Animals↗
PubMed1992

Biochemical studies on oral toxicity of ricin. V. The role of lectin activity in the intestinal absorption of ricin.

In order to investigate a possible role of lectin activity of ricin in its absorption from the small intestine, we prepared two ricin derivatives. BMH-ricin, prepared by crosslinking A and B chains of ricin with 1,6-bismaleimidohexane, was nearly non-toxic but the lectin activity was unaltered. And, NBS-ricin, prepared by the oxidation of tryptophanyl residues of ricin with N-bromosuccinimide, was not only non-toxic but also non-lectinic. After the oral administration of ricin derivatives to rats, their interaction with the digestive tract and absorption into the circulatory systems have been compared with those of ricin, immunochemically and histologically. It was shown by immunostaining that ricin and BMH-ricin could bind to the intestinal mucosa, whereas NBS-ricin could not. No appreciable damage in the small intestine from rats treated with either BMH-ricin or NBS-ricin has been observed, in contrast to ricin treatment where severe impairment of the small intestinal tissues resulted after 5 h. Immunoreactive ricin in the liver has been determined with the ricin enzyme immunoassay (EIA). When compared at 48 h after oral administration, NBS-ricin was not detected, whereas BMH-ricin was found to be 38 micrograms/liver and ricin 100 micrograms/liver. From these results, it was inferred that the lectin activity of ricin plays an important role in the absorption of ricin from the small intestine and that the absorption of ricin protein was enhanced by its high toxicity.

Administration, Oral↗
PubMed1991

Assessment of ligand effects in intracellular trafficking of ricin A chain using anti-ricin hybridomas.

Intracellular ricin and immunotoxin trafficking has been difficult to study as only one to two cytosolic ricin A chain (RTA) molecules are sufficient to cause cell death. Previous studies (R.J. Youle and M. Colombatti, J. Biol. Chem., 262: 4676-4882, 1987) using anti-ricin hybridomas identified the secretory pre-Golgi as a critical site for RTA intoxication. We used ricin and RTA immunotoxins constructed with transferrin (TF) or anti-murine TF receptor antibody (RI7/217) to compare patterns of cytotoxicity and intracellular trafficking in anti-ricin hybridomas. Anti-RTA and anti-ricin B chain (RTB) hybridomas bound similar amounts of ricin and secreted comparable amounts of anti-ricin immunoglobulin. Anti-RTA hybridomas were 50- to 500-fold more resistant to ricin than nonsecretory and anti-RTB hybridomas, defining a ricin-resistant phenotype. All hybridomas expressed similar levels of surface TF receptors. RTA immunotoxins were constructed using human TF or RI7/217 and a disulfide linker. In protein synthesis inhibition assays, ricin-resistant hybridomas were manyfold more resistant to RI7/217-RTA than were ricin-sensitive hybridomas. In contrast, all hybridomas were equally sensitive to TF-RTA. Monensin increased ricin cytotoxicity minimally against all hybridomas, but dramatically increased RI7/217-RTA cytotoxicity in ricin-resistant and ricin-sensitive hybridomas in a way that abrogated the ricin-resistant phenotype. In contrast, monensin increased TF-RTA cytotoxicity equally in all hybridomas. Ammonium chloride had little effect on ricin or RI7/217-RTA cytotoxicity, but increased TF-RTA cytotoxicity against all hybridomas. Taken together, these results suggest that RTA molecules mediating cytotoxicity pass through an anti-RTA antibody-containing pre-Golgi compartment when bound to RTB or RI7/217, but not when bound to TF. Monensin abrogates the ricin-resistant phenotype when RTA is linked to RI7/217, but not RTB. This suggests that monensin alters RI7/217-RTA processing proximal to the pre-Golgi and that passage through the pre-Golgi may not be necessary for translocation of RTA to the cytoplasm. Ammonium chloride alters toxin cytotoxicity only when RTA is linked to TF, suggesting that only TF trafficks RTA through an acid-sensitive compartment prior to cytoplasmic translocation. With the addition of potentiating agents, each toxin studied showed a unique cytotoxicity profile against the anti-ricin hybridomas, demonstrating a dominant role of the cell binding ligand in intracellular toxin trafficking.

Ammonium Chloride↗
PubMed1987

Whole ricin and recombinant ricin A chain idiotype-specific immunotoxins for therapy of the guinea pig L2C B cell leukemia.

The therapeutic efficacy of whole ricin, or recombinant ricin A chain, coupled to a monoclonal antibody that reacts with the idiotype of the surface IgM expressed on guinea pig L2C lymphoblasts, was assessed. In vitro studies were done to characterize the immunotoxins (IT) and to demonstrate their specificity before use in vivo. The concentration of whole ricin IT (M6-Ricin) that inhibited protein synthesis by 50% (IC50) in L2C cells was 1.4 X 10(-9) M, in a 5-hr assay, in the presence of lactose to block non-antibody-directed toxicity. M6-Ricin did not inhibit protein synthesis in two control guinea pig cell lines that did not express the idiotype, nor did a whole ricin IT prepared with an isotype-matched monoclonal antibody of irrelevant specificity inhibit protein synthesis in L2C cells. Two recombinant ricin A chain IT, which differed from one another by a factor of 2 to 3 in the number of A chains conjugated per antibody molecule, were less effective in vitro than M6-Ricin (IC50 of greater than 5 X 10(-8) M). For in vivo experiments, the IT were given by the i.p. route 24 hr after the i.p. inoculation of 1 X 10(5) L2C cells. The highest doses of M6-Ricin and M6-Ricin A chain IT tested, 30 micrograms/kg and 3000 micrograms/kg, respectively, were within fourfold to fivefold of their maximum tolerated doses; no deaths or ill effects due to ricin toxicity were noted. These doses increased the median survival time of L2C-bearing guinea pigs to 31 to 34 days, compared with 15 days for untreated animals. This magnitude of increase in survival indicates that 99.999% (5 logs) of injected tumor cells were eliminated, thus accounting for the 12% long-term survival rate obtained. Median survival times for guinea pigs treated with 30 micrograms/kg of the A chain IT were 18 and 21 days for the two conjugates tested, and the median survival for guinea pigs treated with 3000 micrograms/kg of unconjugated antibody was 18 days. Our data demonstrate that recombinant A chain IT are active in vivo and that the B chain of ricin can potentiate IT activity in vivo. Although the potency differs by 100-fold, the therapeutic index of the intact ricin IT is similar to that of the ricin A chain IT.

Animals↗
PubMed1987

Hybridoma cells containing intracellular anti-ricin antibodies show ricin meets secretory antibody before entering the cytosol.

Hybridoma cells which synthesize monoclonal antibodies (mAb) that block ricin toxicity were 50-300-fold resistant to ricin compared with other hybridomas. Two of the mAb blocked two isozymes of ricin, D and E, to different and opposite extents, and the hybridoma cell resistance to the two forms of ricin closely corresponded with the mAb reactivity. The hybridoma cell resistance to ricin was therefore due to the binding activity of the mAb produced by the cells. Neither rabbit polyclonal antibodies, which neutralized extracellular anti-ricin mAb, nor quantitative removal of hybridoma cell surface IgG with papain affected the cellular resistance to ricin. Therefore, neither extracellular or cell surface antibodies contributed to the resistance of the hybridoma cells. In contrast, inhibition of protein synthesis by cycloheximide or puromycin, which selectively decreased levels of intracellular secretory IgG, decreased the hybridoma cell resistance to ricin. We conclude that intracellular mAb, synthesized de novo for subsequent secretion, block ricin toxicity. Ricin therefore must meet intracellular secretory antibodies before reaching the cytosol. The monoclonal antibodies can also be used to study toxin function within intracellular compartments. An antibody specific for the galactose-binding site of ricin blocks ricin intracellularly, showing that the ricin galactose-binding activity is required in an intracellular compartment for transport of ricin A chain to the cytosol.

Animals↗
PubMed1992

Biochemical studies on oral toxicity of ricin. IV. A fate of orally administered ricin in rats.

After oral administration of ricin in rats, its distribution in the gastrointestinal tract, body fluids and principal organs was determined by an enzyme immunoassay, and the immunoreactive ricin detected was identified by gel filtration followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis, protein blotting and the immunobinding method. When ricin D (10 mg/kg rat) was given orally to a rat, which dose is equivalent to 1/3 LD50, about 75% of the ricin was found in the stomach and small intestine within 2 h, and most of it was transferred to the large intestine after 24 h. It was also demonstrated by an in vitro toxicity test of immunoreactive ricin in the blood and lymph obtained from the intoxicated rats that a part of the ricin was absorbed from the small intestine into the tissues and organs via the circulatory systems (lymphatic and blood vessels) as the active ricin. The participation of the blood vessels was greater in the absorption of ricin from the gastrointestinal tract than that of the lymphatic system. Ricin, after absorption, was detected in liver and spleen and ricin found in the liver was predominantly in the form of intact ricin, although an undetectable amount of ricin in other organs cannot be eliminated. These results infer that a small fraction of orally-given ricin was transferred to the circulating system and was responsible for rat's death as in the case of i.p. administration.

Administration, Oral↗
PubMed1982

Preparation and properties of chimeric toxins prepared from the constituent polypeptides of diphtheria toxin and ricin. Evidence for entry of ricin A-chain via the diphtheria toxin pathway.

A highly toxic conjugate of ricin A-chain and diphtheria toxin fragment B was prepared by disulfide exchange reaction. A similar conjugate between diphtheria toxin fragment A and ricin B-chain was nontoxic. Like native diphtheria toxin, the conjugate ricin A/diphtheria toxin B was much more toxic to Vero than to HeLa cells. Ricin was equally toxic to these cell lines. Lactose, which inhibits ricin binding, did not protect against the conjugate. Cells resistant to ricin, partly due to a reduced number of ricin-binding sites, were fully sensitive to the conjugate, indicating that the conjugate binds to diphtheria toxin receptors. The conjugate was fully toxic to two Vero cell mutants, resistant to diphtheria toxin because the elongation factor 2 could not be ADP-ribosylated by the diphtheria toxin A-fragment. Therefore, the inhibition of protein synthesis by the conjugate must be caused by the ricin A-chain. Ammonium chloride which prevents entry of diphtheria toxin, but not of ricin, also protected against the conjugate. Like diphtheria toxin, the conjugate was most toxic at low pH, whereas ricin is most active at pH above neutrality and inactive at low pH. The results indicate that the conjugate ricin A/diphtheria toxin B binds to diphtheria toxin receptors and inhibits cellular protein synthesis due to the action of ricin A-chain which appears to enter the cell by the diphtheria toxin pathway.

Ammonium Chloride↗
PubMed1992

Blocked ricin-conjugated T cell immunotoxins: effect of anti-CD6-blocked ricin on normal T cell function.

The biological properties of an immunotoxin composed of an anti-CD6 monoclonal antibody conjugated to whole ricin, which had been modified so that the galactose-binding sites of the B chain were blocked ("blocked ricin"), were examined. Treatment of peripheral blood lymphocytes with anti-CD6-blocked ricin for a 24-h period prevented T cell proliferation induced by phytohemagglutinin in a dose-dependent manner with concentrations causing 50% inhibition (IC50) ranging from 5 pM to 30 pM. In contrast, treatment with either blocked ricin alone or with a control immunotoxin prepared with a B-cell-lineage-restricted monoclonal antibody gave IC50 values of approximately 2 nM. Although shortening the duration of the anti-CD6-blocked ricin treatment to as little as 3 h had little significant effect on the observed inhibition, T cell viability experiments demonstrated that the magnitude of immunotoxin-induced killing after a given time period is significantly higher when the target cells become activated. Thus, from the initial concentration of cells treated with anti-CD6-blocked ricin placed in culture, 40%-45% viable cells remained after 2 days yet only 3%-9% remained if phorbol ester and Ca2+ ionophore were added; activation of T cells after mock treatment using blocked ricin plus nonconjugated anti-CD6 demonstrated that this effect was not the result of activation alone. The toxicity of anti-CD6-blocked ricin was also measured by inhibition of PHA-induced clonogenic growth of normal T cells. Continuous treatment of the cells using anti-CD6-blocked ricin at 0.1 nM resulted in a surviving fraction of about 3.5 x 10(-3); when immunotoxin treatment was for 24 h or less, the surviving fraction was only about 10(-1). As an indication of the unique specificity of anti-CD6-blocked ricin, immunotoxin pretreatment of potential responder cells prevented the generation of allogeneic cytolytic T lymphocytes in mixed lymphocyte cultures yet had little effect on the generation of interleukin-2-induced lymphokine-activated killer cell activity. We conclude that anti-CD6-blocked ricin demonstrates a cellular specificity and potency that make it a highly promising anti-T cell reagent.

Antigens, CD↗
PubMed1984

Osmotically induced microinjection of ricin bypasses a ricin internalization defect in a Chinese hamster ovary mutant cell line.

By osmotic lysis of pinocytic vesicles we were able to inject ricin or ricin A chain directly into the cytosol of Chinese hamster ovary cells. The lag time of 1 to 2 h before the onset of the inhibition of protein synthesis by ricin in intact cells was reduced to 15 to 30 min by this method. Preincubation of cells with a low concentration of nigericin, which was shown earlier to enhance the cytotoxicity of ricin, had no effect under this condition. Direct transfer of either intact ricin or the ricin A subunit by osmotic lysis of pinocytic vesicles into the cytosol of the ricin-resistant CHO mutant cell line 4-10 rendered the mutant 4-10 cells as sensitive to ricin as the CHO pro wild-type cells. Both the lag time and the rate of inhibition of protein synthesis in the wild-type and mutant cell lines after the introduction of ricin by osmotic lysis of pinocytic vesicles were the same. These results indicate that injection of ricin into the cytosol by osmotic lysis of pinosomes bypasses the internalization defect in the mutant cell line.

Animals↗
PubMed1986

Mannose receptor-mediated uptake of ricin toxin and ricin A chain by macrophages. Multiple intracellular pathways for a chain translocation.

The role of the high mannose carbohydrate chains in the mechanism of action of ricin toxin was investigated. Ricin is taken up by two routes in macrophages, by binding to cell surface mannose receptors, or by binding of the ricin galactose receptor to cell surface glycoproteins. Removal of carbohydrate from ricin by periodate oxidation led to a large loss in toxicity via both routes of uptake by an effect on the B chain not due to a loss of galactose binding affinity. These data suggest that the carbohydrate chains of ricin B chain may be required for full toxicity. The pathway of uptake of ricin by the macrophage mannose receptor was found to differ in several respects from uptake via the galactose-specific pathway. Analysis of intoxication of macrophages by ricin in the presence of ammonium chloride suggested that mannose receptor bound ligand passes through acidic vesicles prior to translocation, unlike galactose bound ligand. Intoxication by ricin via galactose-specific uptake was potentiated by swainsonine but not by castanospermine, suggesting that ricin may be attacked by an endogenous mannosidase within the cell, and that ricin passes through either a lysosomal or a Golgi compartment prior to translocation.

Ammonium Chloride↗
PubMed1986

Routing of internalized ricin and ricin conjugates to the Golgi complex.

Receptor-mediated endocytosis and intracellular routing of native ricin, and of ricin conjugated to colloidal gold (Ri-Au) and to horseradish peroxidase (Ri-HRP), have been studied in cultured MCF-7 and Vero cells by electron microscopical techniques including serial section analysis. Both native ricin, as demonstrated by immunoperoxidase cytochemistry, and the ricin conjugates were internalized via a common coated pit-coated vesicle pathway to reach vacuolar and tubulo-vesicular portions of the endosomal system. In addition, native ricin and a purified monovalent fraction of Ri-HRP reached distinct Golgi cisterns, whereas Ri-Au and polyvalent Ri-HRP did not. The results delineate intracellular routing of native ricin and compare it with the routing of different ricin conjugates. Moreover, our study shows that conjugates of a particular ligand (ricin) and various probes (e.g., gold and peroxidase), may be handled differently by cells. Sorting apparently takes place in the endosomal system, allowing some but not other molecules to reach Golgi elements. This sorting seems to depend on the valency of the ricin conjugate.

Biological Transport↗
PubMed1984

Monoclonal antibody-toxin conjugates reactive against human T lymphocytes. A comparison of antibody linked to intact ricin toxin with antibody linked to ricin A chain.

A non-complement-binding monoclonal antibody, TA-1, recognizing determinants on human T lymphocytes, was linked to the plant seed toxin ricin, either the intact molecule or purified ricin A chain. Peripheral blood lymphocytes were pretreated with conjugate for 2 hr, washed, and then measured in vitro for T cell proliferation. Studies showed that antibody-intact ricin conjugates were up to 39-fold more inhibitory than antibody-A-chain conjugates. Killing was selective because an unreactive control antibody linked to toxin had minimal inhibitory effect. Dose response curves obtained in human studies were nearly identical to curves obtained in an animal model n which a monoclonal anti-murine T cell antibody (anti-Thy 1.1) was linked to ricin and ricin A chain. In the human system, longer exposures of peripheral blood cells to conjugates did not alter our findings. TA-1-ricin conjugates were tested against human ALL cell lines. KOPN-1, a cell line bearing the determinant reactive with TA-1 was selectively eliminated within 2 days after pretreatment with 500 ng/ml. Even 10-fold greater concentrations of TA-1-A chain were not adequate for leukemic cell destruction. These findings (1) show for the first time in a human model that monoclonal antibodies, directed against certain differentiation antigens when linked to ricin A chain are not as effective in normal or malignant cell killing as when linked to intact ricin; (2) contribute to the growing body of evidence showing that monoclonal antibody A chain conjugates do not permit the acquisition of levels of toxin sufficient to destroy target cells; and (3) are important relative to increasing interest in use of antibody-toxin conjugates for graft-versus-host disease prophylaxis in allogeneic bone marrow transplantation.

Antibodies, Monoclonal↗
PubMed1989

Distribution of ricin within the mammalian para-aortic lymph node. II. Comparison of the localization, after intramuscular dosage of colloidal gold-labelled ricin in vivo, with in vitro binding characteristics of the native toxin.

Previous work has shown that, following an intramuscular injection of ricin, the toxin becomes localized within histiocytes in the sinuses of lymph nodes draining the 'wound' site. When ricin labelled with colloidal gold was similarly injected, it was found within the same lymphoid cells as seen with native ricin. Biologically inert Indian ink apparently follows a similar fate, as demonstrated by the appearance of carbon particles within sinus histiocytes, as soon as 1 h after intramuscular injection. When the binding in vitro of Indian ink or ricin toxin to sections of lymph node was examined, ricin was seen to bind to the surfaces of the same sinusoidal cells and also, with a much lower frequency, to follicular lymphocytes, whereas Indian ink failed to bind. This indicated an interaction between ricin and cell membrane components. Moreover, this binding was inhibited markedly by the galactose-containing disaccharide, lactose, a target sugar specified by the lectin binding site of ricin and to a much lesser extent by the monosaccharide mannose.

Animals↗