1998
DOI: 10.1021/bc970192w
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Role of Cross-Linking Agents in Determining the Biochemical and Pharmacokinetic Properties of Mgr6−Clavin Immunotoxins

Abstract: 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 proced… Show more

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Cited by 15 publications
(11 citation statements)
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“…Indeed, in vivo blood circulation stability has been shown to be as little as 4hrs for disulfide-based immunotoxin-antibody conjugates, with circulation stability directly dependent on glutathione reduction kinetics. 7,33,34 Accordingly, the decreased rate of the retro reaction of the maleimide-thiol adduct with glutathione would increase compound circulation stability while maintaining cleavage sensitivity in highly reducing environments.…”
Section: Resultsmentioning
confidence: 99%
“…Indeed, in vivo blood circulation stability has been shown to be as little as 4hrs for disulfide-based immunotoxin-antibody conjugates, with circulation stability directly dependent on glutathione reduction kinetics. 7,33,34 Accordingly, the decreased rate of the retro reaction of the maleimide-thiol adduct with glutathione would increase compound circulation stability while maintaining cleavage sensitivity in highly reducing environments.…”
Section: Resultsmentioning
confidence: 99%
“…The disulfide linkage between the peptides and the polymers is expected to be sterically hindered because of the presence of the bulky polymer chain and the amino acids adjacent to the cysteine moiety. The incorporation of bulky groups next to the disulfide linkages, such as the methyl and benzene ring instead of Hs, was shown to reduce the reaction rate with the thiolate anion and increase the linkage stability 35, 36. Accordingly, amino acids lacking bulky side groups (e.g., glycine) are expected to present a more favorable environment for the access of the thiolate anion to the disulfide linkage.…”
Section: Resultsmentioning
confidence: 99%
“…The disulfide bridge is reduced inside the cell, whereupon the effector domain of the molecule leaves the vesicle and exerts its action. The effect of the protein on cellular components is eliminated or weakened when the disulfide bridge is replaced with a thioether bridge (for instance, [23]). Similarly in our experiments, the reducible disulfide conjugate restored the transmitter release of TET‐intoxicated cells, while the non‐reducible thioether conjugate was inefficient.…”
Section: Discussionmentioning
confidence: 99%