Preclinical safety and efficacy studies with an affinity-enhanced epithelial junction opener and PEGylated liposomal doxorubicin.

Maximilian Richter; Roma Yumul; Hongjie Wang; Kamola Saydaminova; Martin Ho; Drew May; Audrey Baldessari; Michael Gough; Charles Drescher; Nicole Urban; Steve Roffler; Chloé Zubieta; Darrick Carter; Pascal Fender; André Lieber

doi:10.1038/mtm.2015.5

Article dans une revue

Preclinical safety and efficacy studies with an affinity-enhanced epithelial junction opener and PEGylated liposomal doxorubicin.

Maximilian Richter ¹ Roma Yumul ¹ Hongjie Wang ¹ Kamola Saydaminova ¹ Martin Ho ¹ Drew May ² Audrey Baldessari ² Michael Gough ² Charles Drescher ³ Nicole Urban Steve Roffler Chloé Zubieta ^{4, 5} Darrick Carter ^{6, 1} Pascal Fender ⁷ André Lieber ¹

1 Division of Medical Genetics [Seattle]

2 Washington National Primate Research Center [Seattle]

3 ILL - Institut Laue-Langevin

4 LPCV - Laboratoire de physiologie cellulaire végétale

5 Laboratoire de Physiologie Cellulaire and Végétale - UMR5168

6 Health and Safety Executive

7 IBS - UMR 5075 - Institut de biologie structurale

Abstract : A central treatment resistance mechanism in solid tumors is the maintenance of epithelial junctions between malignant cells that prevent drug penetration into the tumor. We have developed a small recombinant protein (JO-1) that triggers the transient opening of intercellular junctions and thus increases the efficacy of monoclonal antibodies and chemotherapeutic drugs without causing toxicity in mouse tumor models. Here, we provide data toward the clinical translation of an affinity-enhanced version of JO-1, which we call JO-4, in combination with PEGylated liposomal doxorubicin (PLD)/Doxil for ovarian cancer therapy. We have presented X-ray crystallography data suggesting a structural basis for the higher affinity of JO-4 to DSG2. We also confirmed JO-4 efficacy in a xenograft model with primary ovarian cancer cells showing that JO-4 can salvage Doxil therapy when given at a dose that was threefold lower than the therapeutic dose. Furthermore, we tested the safety of intravenous JO-4 alone and in combination with Doxil in Macaca fascicularis, an adequate animal model for predicting toxicity in humans. Our studies did not show critical JO-4-related toxicity or an increase of Doxil-related side effects. Our efficacy and safety data will help to support an Investigational new drug-filing for a JO-4/Doxil combination treatment.

Type de document :

Article dans une revue

Domaine :

Sciences du Vivant [q-bio] / Biochimie, Biologie Moléculaire / Biologie structurale [q-bio.BM]

Liste complète des métadonnées

https://hal.univ-grenoble-alpes.fr/hal-01162665
Contributeur : Frank Thomas <>
Soumis le : jeudi 11 juin 2015 - 10:30:21
Dernière modification le : jeudi 26 novembre 2020 - 08:30:03