Immunotoxins of pseudomonas exotoxin A (PE): Effect of linkage on conjugate yield, potency, selectivity and toxicity

Morgan, Alton C.; Sivam, Gowsala; Beaumier, Paul L.; McIntyre, Robert; Bjorn, Mike; Abrams, Paul G.

doi:10.1016/0161-5890(90)90140-u

Cited by 18 publications

(5 citation statements)

References 24 publications

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“…The poor in vivo potency of the disulfide BR64-DOX conjugates may have resulted from the instability of the disulfide linker [Trail et al, 19921. Other investigators have reported that immiinotoxins prepared with hindered-disulfide bonds were both more stable and more active in vivo than those prepared with disulfide bonds [Thorpe et al, 1987;Worrell et al, 1986;Candiani et al, 199.21. Similarly, thioetherlinked immunoconjugates were shown to be more stable in vivo than the corresponding disulfide-linked conjugates [Koizumi et al, 1987[Koizumi et al, , 1988Peeters et al, 1989;Morgan et al, 1990;Vitetta and Thorpe, 19911. Both thc poor potency and small therapeutic index of RR64-DOX disulfide conjugates were likely due to systemic release of D O X following reduction of the labile disiilfide bond [Trail et al, 19921.…”

Section: Acid-labile Linkers: Hydrazonesmentioning

confidence: 99%

Site‐directed delivery of anthracyclines for treatment of cancer

Trail

Willner

Hellström

1995

Drug Development Research

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The efficacy of cancer treatment is often limited by the lack of selectivity of anticancer agents for malignant cells. A promising approach for increasing both the efficacy and therapeutic index of anticancer agents i s to utilize antibodies, directed against tumor-associated antigens, t o selectively deliver anticancer agents to tumor cells. Antibodies have been used t o deliver a variety of anticancer agents including chemotherapeutic drugs, plant and bacterial toxins, and radionuclides. This review concentrates on the chemistry and preclinical biology o f immunoconjugates made with members of the anthracycline group of antibiotics. o 1995 WiIey-Liss, Inc.

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Section: Acid-labile Linkers: Hydrazonesmentioning

confidence: 99%

Site‐directed delivery of anthracyclines for treatment of cancer

Trail

Willner

Hellström

1995

Drug Development Research

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“…The coupling method used may affect the activity of the resulting conjugates (Edwards, 1983;Morgan et al, 1990). Our study showed that the NR-ML-05-abrin conjugate prepared by the SPDP method displayed a lower potency and ability to bind than when the SMCC method was used.…”

Section: Discussionmentioning

confidence: 85%

“…Previous studies have shown that the type of antibody-toxin linkage may affect not only the in vivo stability of ITS (Morgan et al, 1990), but also their potency and specificity in vitro. Our purpose was to explore whether 2 conjugation methods that involve different treatments of the antibody moiety may differentially affect the binding of the conjugates to the target cells.…”

Section: Role Of Conjugation Methodsmentioning

confidence: 99%

Immunotoxins directed against the high‐molecular‐weight melanoma‐associated antigen. Identification of potent antibody‐toxin combinations

Godal

Kumle

Pihl

et al. 1992

Intl Journal of Cancer

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To study factors influencing the cytotoxicity of immunotoxins (ITs), we compared the in vitro cytotoxicity of conjugates in which the plant toxin abrin and the bacterial toxin Pseudomonas exotoxin A (PE) were coupled by 2 different procedures to 2 MAbs, 9.2.27 and NR-ML-05, which bind to different epitopes on the melanoma-associated antigen p250. The individual target cell lines differed widely in sensitivity to the different ITs, as assessed by measurement of protein synthesis inhibition. The action of the ITs was highly specific, as the toxicity of abrin and PE conjugates was respectively 20-540 and 2,200-550,000 times higher in antigen-positive cell lines (FEMX, SESX, OHS) than in the antigen-negative line KPDX. The PE conjugates prepared with the 2 different MAbs differed in potency by factors of 16-126 in the target-cell lines, but were consistently more toxic than the abrin ITs. The results demonstrate that the cytotoxicity of ITs varies with the nature of both of its moieties and that optimal results require that toxins and MAbs be matched. Moreover, the 2 coupling procedures affected differentially the binding and potency of some ITs. Each of the 2 toxins was conjugated to a sheep anti-mouse antibody (SAM) and the toxicity of these 2 conjugates was tested in an indirect approach using 9.2.27 and NR-ML-05 as primary MAbs. The results showed that the indirect procedure would have correctly predicted the most potent antibody-toxin pair, indicating that the approach may be valid for selecting suitable combinations of MAbs and toxins for use as direct ITs.

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“…(Lambert et al, 1991a,b). Native PE was conjugated to SEN7 via a thioether linkage (Morgan et al, 1990;FitzGerald et al, 1990 (Olsnes et al, 1989;Sandvig et al, 1991), translocation of PE seems to be confined to the endoplasmic reticulum (FitzGerald & Pastan, 1992). In view of recent progress in enhancing the potentiating effect of monensin in vivo (Hertler et al, 1989;Griffin et to SEN7-bR but were more than 10-fold less susceptible to intoxication by PE.…”

Section: Potentiation Of Immunotoxinsmentioning

confidence: 99%

“…Blocked ricin (bR) is a derivative in which the galactose binding sites of the B-chain are blocked by chemical modification resulting in a 3,500-fold lower binding affinity (Lambert et al, 1991a,b). With PE modification occurs most efficiently when the MAb is coupled to domain I via a thioether linkage which sterically blocks its cell-binding activity (Morgan et al, 1990;FitzGerald et al, 1990). Both bR and PE blocked by a thioether linkage have intact translocation and catalytic domains.…”

mentioning

confidence: 99%

Immunotoxins recognising a new epitope on the neural cell adhesion molecule have potent cytotoxic effects against small cell lung cancer

Zangemeister‐Wittke

Collinson²,

Frösch³

et al. 1994

Br J Cancer

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Summary The present study describes a comparison of two potent immunotoxins which utilise an identical targeting component, a monoclonal antibody (SEN7) specific for small cell lung cancer (SCLC), conjugated to two different effector components, blocked ricin (bR) and Pseudomonas exotoxin A (PE). SEN7 recognises a novel epitope on the neural cell adhesion molecule (NCAM) which is highly associated with SCLC. The immunotoxins SEN7-PE and SEN7-bR were selectively and potently active against a number of SCLC cell lines, of both classic and variant morphologies, inhibiting the incorporation of [3H]leucine with IC50 values ranging between 22 pM and 85 pM and between 7 pM and 62 pM for SEN7-PE and SEN7-bR respectively. Intoxication by both immunotoxins proceeded rapidly following short 2 h lag phases; the initial rates of protein synthesis inhibition occurred with t50 values of 6.5 h for SEN7-PE and 5.5 h for SEN7-bR. Monensin drastically enhanced the cytotoxic activity of the weakly active SEN7-ricin A-chain by 2,100-fold and of SEN7-bR by 80-fold but had no effect on SEN7-PE. In limiting dilution assays, four and more than 4.5 logs of clonogenic SW2 tumour cells were selectively eliminated from the cultures during continuous exposure to the immunotoxins SEN7-PE and SEN7-bR respectively, while antigen-negative cells required up to 1,000-fold more drug for a similar cell kill. SW2 cells surviving SEN7-bR treatment in the cultures did not express NCAM and consequently were not selectively killed by SEN7 immunotoxins. SW2 cells surviving continuous exposure to SEN7-PE showed no alteration in NCAM expression but were more resistant to intoxication mediated by PE. These cells were still sensitive to SEN7-bR.

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Immunotoxins of pseudomonas exotoxin A (PE): Effect of linkage on conjugate yield, potency, selectivity and toxicity

Cited by 18 publications

References 24 publications

Site‐directed delivery of anthracyclines for treatment of cancer

Site‐directed delivery of anthracyclines for treatment of cancer

Immunotoxins directed against the high‐molecular‐weight melanoma‐associated antigen. Identification of potent antibody‐toxin combinations

Immunotoxins recognising a new epitope on the neural cell adhesion molecule have potent cytotoxic effects against small cell lung cancer

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