Selective Antitumor Effect of Thioether-Linked Immunotoxins Composed of Gelonin and Monoclonal Antibody to Alpha-Fetoprotein or Its F(ab&lt;sup&gt;/&lt;/sup&gt;)Fragment

Masuda, Kazuyoshi; Takahashi, Koji; Hirano, Kazuyuki; Takagishi, Yasushi

doi:10.1159/000217889

Cited by 5 publications

(2 citation statements)

References 6 publications

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“…Morever, for RIPs with a ribonuclease action, the maintenance of an intracellular easily breakable linkage between mAb and RIP is essential. This behavior is consistent with that described for gelonin and RTA (44) but in contrast with other findings (45) which suggested that gelonin can be delivered efficently by a thioether linkage with the appropriate anti-R-fetoprotein antibody.…”

Section: Discussionsupporting

confidence: 91%

Role of Cross-Linking Agents in Determining the Biochemical and Pharmacokinetic Properties of Mgr6−Clavin Immunotoxins

Dosio¹,

Berlier²,

Adobati³

et al. 1998

Bioconjugate Chem.

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Several immunotoxins (ITs) were synthesized by the attachment of clavin, a recombinant toxic protein derived from Aspergillus clavatus, to the monoclonal antibody Mgr6 that recognizes an epitope of the gp185(HER-2) extracellular domain expressed on breast and ovarian carcinoma cells. Conjugation and purification parameters were analyzed in an effort to optimize the antitumor activity and stability of the ITs in vivo. To modulate the in vitro and in vivo properties of the immunotoxins, different coupling procedures were used and both disulfide and thioether linkages were obtained. Unhindered and hindered disulfide with a methyl group linkage ethyl S-acetyl 3-mercaptopropionthioimidate ester hydrochloride (AMPT) or ethyl S-acetyl 3-mercaptobutyrothioimidate ester hydrochloride (M-AMPT) were obtained by reaction with recombinant clavin, while the monoclonal antibody Mgr6 was derivatized with ethyl 3-[(4-carboxamidophenyl)dithio]propionthioimidate ester hydrochloride (CDPT). To achieve higher hindrance (a disulfide bond with a geminal dimethyl group), Mgr6 was derivatized with the N-hydroxysuccinimidyl 3-methyl-3-(acetylthio)butanoate (SAMBA) and clavin with CDPT. To evaluate the relevance of the disulfide bond in the potency and pharmacokinetic behavior of the ITs, a conjugate consisting of a stable thioether bond was also prepared by derivatizing Mgr6 with the N-hydroxysuccinimidyl ester of iodoacetic acid (SIA) and clavin with AMPT. The immunotoxins were purified and characterized using a single-step chromatographic procedure. Specificity and cytotoxicity were assayed on target and unrelated cell lines. The data indicate that the introduction of a hindered disulfide linkage into ITs has little or no effect on antitumor activity and suggest that disulfide cleavage is essential for activity; indeed, the intracellularly unbreakable thioether linkage produced an inactive IT. Analysis of IT stability in vitro showed that the release of mAb by incubation with glutathione is proportional to the presence of methyl groups and increases exponentially with the increase in steric hindrance. Analysis of the pharmacokinetic behavior of ITs in Balb/c mice given intravenous bolus injections indicated that ITs with higher in vitro stability were eliminated more slowly; i.e., the disulfide bearing a methyl group doubled the beta-phase half-life (from 3.5 to 7.1 h) compared with that of the unhindered, while a geminal dimethyl protection increased the elimination phase to 24 h. The thioether linkage showed its intrinsic stability with a beta-phase half-life of 46 h. The thioether linkage also increased the distribution phase from 17 to 32 min. The in vitro characteristics and in vivo stability of Mgr6-clavin conjugates composed of a methyl and dimethyl steric hindered disulfide suggest clinical usefulness.

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Section: Discussionsupporting

confidence: 91%

Role of Cross-Linking Agents in Determining the Biochemical and Pharmacokinetic Properties of Mgr6−Clavin Immunotoxins

Dosio¹,

Berlier²,

Adobati³

et al. 1998

Bioconjugate Chem.

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“…The selected toxin can be a bacterial toxin such as Pseudomonas exotoxin, diphtheria toxin, or shiga toxin and also can be a plant toxin such as ricin, saporin, and gelonin. The initial immunotoxin studies on hepatoma cells were based on plant toxins including trichosanthin and gelonin toxins in 1991 and 1994, respectively [23,24]. These studies gave promising results about the potent and quite specific anti-hepatoma agents.…”

Section: Immunotoxinsmentioning

confidence: 99%

Immunotoxins Immunotherapy against Hepatocellular Carcinoma: A Promising Prospect

Heiat

Yeganeh

Alavian

et al. 2021

Toxins

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Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. Therefore, fighting against such cancer is reasonable. Chemotherapy drugs are sometimes inefficient and often accompanied by undesirable side effects for patients. On the other hand, the emergence of chemoresistant HCC emphasizes the need for a new high-efficiency treatment strategy. Immunotoxins are armed and rigorous targeting agents that can purposefully kill cancer cells. Unlike traditional chemotherapeutics, immunotoxins because of targeted toxicity, insignificant cross-resistance, easy production, and other favorable properties can be ideal candidates against HCC. In this review, the characteristics of proper HCC-specific biomarkers for immunotoxin targeting were dissected. After that, the first to last immunotoxins developed for the treatment of liver cancer were discussed. So, by reviewing the strengths and weaknesses of these immunotoxins, we attempted to provide keynotes for designing an optimal immunotoxin against HCC.

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Alternative Treatment Approaches to Early Stage or Unresectable Hepatocellular Carcinoma Confined to the Liver

Izzo¹,

Fiore²,

Werra³

et al. 1998

Liver Cancer

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Selective Antitumor Effect of Thioether-Linked Immunotoxins Composed of Gelonin and Monoclonal Antibody to Alpha-Fetoprotein or Its F(ab<sup>/</sup>)Fragment

Cited by 5 publications

References 6 publications

Role of Cross-Linking Agents in Determining the Biochemical and Pharmacokinetic Properties of Mgr6−Clavin Immunotoxins

Role of Cross-Linking Agents in Determining the Biochemical and Pharmacokinetic Properties of Mgr6−Clavin Immunotoxins

Immunotoxins Immunotherapy against Hepatocellular Carcinoma: A Promising Prospect

Alternative Treatment Approaches to Early Stage or Unresectable Hepatocellular Carcinoma Confined to the Liver

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