Releasable PEGylation of Mesothelin Targeted Immunotoxin SS1P Achieves Single Dosage Complete Regression of a Human Carcinoma in Mice
| Autor: | Karen Yang, David J. FitzGerald, Gerald Petti, Raffit Hassan, Deshan Yu, Dechun Wu, Hong Zhao, Zhenfan Zhang, Robert J. Kreitman, Amartya Basu, Ahsen Janjua, Qing-cheng Wang, Zhihua Zhang, Laiman Xiang, Mitchell Ho, Jun Liu, Xiguang Li, Clifford Longley, John Zhou, David Filpula, Richard Beers, Ira Pastan, Maoliang Wang, Ping Peng |
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| Rok vydání: | 2007 |
| Předmět: |
Biomedical Engineering
Pharmaceutical Science Bioengineering Pharmacology GPI-Linked Proteins Polyethylene Glycols Mice Pharmacokinetics In vivo Immunotoxin PEG ratio Animals Humans Potency Mesothelin Cytotoxicity Mice Inbred BALB C Membrane Glycoproteins biology Chemistry Immunotoxins Carcinoma Organic Chemistry Antibodies Monoclonal Xenograft Model Antitumor Assays Recombinant Proteins PEGylation biology.protein Biotechnology |
| Zdroj: | Bioconjugate Chemistry. 18:773-784 |
| ISSN: | 1520-4812 1043-1802 |
| Popis: | Recombinant immunotoxins exhibit targeting and cytotoxic functions needed for cell-specific destruction. However, antitumor efficacy, safety, and pharmacokinetics of these therapeutics might be improved by further macromolecular engineering. SS1P is a recombinant anti-mesothelin immunotoxin in clinical trials in patients with mesothelin-expressing tumors. We have modified this immunotoxin using several PEGylation strategies employing releasable linkages between the protein and the PEG polymers, and observed superior performance of these bioconjugates when compared to similar PEG derivatives bearing permanent linkages to the polymers. PEGylated derivatives displayed markedly diminished cytotoxicity on cultured mesothelin-overexpressing A431-K5 cells; however, the releasable PEGylated immunotoxins exhibited increased antitumor activity in A431-K5 xenografts in mice, with a diminished animal toxicity. Most significantly, complete tumor regressions were achievable with single dose administration of the bioconjugates but not the native immunotoxin. Pharmacokinetic analysis of the releasable PEGylated derivatives in mice demonstrated an over 80-fold expansion of the area under the curve exposure of bioactive protein when compared to native immunotoxin. A correlation in degree of derivatization, release kinetics, and polymer size with potency was observed in vivo, whereas in vitro cytotoxicity was not predictive of efficacy in animal models. The potent antitumor efficacy of the releasable PEGylated mesothelin-targeted immunotoxins was not exhibited by similar untargeted PEG immunotoxins in this model. Since the bioconjugates can also exhibit the attributes of passive targeting via enhanced permeability and retention, this is the first demonstration of a pivotal role of active targeting for immunotoxin bioconjugate efficacy. |
| Databáze: | OpenAIRE |
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