title: Preclinical safety and efficacy studies with an affinity-enhanced epithelial junction opener and PEGylated liposomal doxorubicin.
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.
authors.affiliation: Division of Medical Genetics, University of Washington , Seattle, Washington, USA.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Richter
authors.affiliation: Division of Medical Genetics, University of Washington , Seattle, Washington, USA.
authors.forename: Roma
authors.initials: R
authors.lastname: Yumul
authors.affiliation: Division of Medical Genetics, University of Washington , Seattle, Washington, USA.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Medical Genetics, University of Washington , Seattle, Washington, USA.
authors.forename: Kamola
authors.initials: K
authors.lastname: Saydaminova
authors.affiliation: Division of Medical Genetics, University of Washington , Seattle, Washington, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Ho
authors.affiliation: Washington National Primate Research Center , Seattle, Washington, USA.
authors.forename: Drew
authors.initials: D
authors.lastname: May
authors.affiliation: Washington National Primate Research Center , Seattle, Washington, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Baldessari
authors.affiliation: Washington National Primate Research Center , Seattle, Washington, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gough
authors.affiliation: Fred Hutchinson Cancer Research Center , Seattle, Washington, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Drescher
authors.affiliation: Fred Hutchinson Cancer Research Center , Seattle, Washington, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Urban
authors.affiliation: Academia Sinica , Taipei, Taiwan.
authors.forename: Steve
authors.initials: S
authors.lastname: Roffler
authors.affiliation: European Synchrotron Radiation Facility , Grenoble, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Zubieta
authors.affiliation: Division of Medical Genetics, University of Washington , Seattle, Washington, USA ; Compliment Corp. , Seattle, Washington, USA.
authors.forename: Darrick
authors.initials: D
authors.lastname: Carter
authors.affiliation: Unit of Virus Host Cell Interactions, UMI3265, CNRS/EMBL/UJF , Grenoble, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Fender
authors.affiliation: Division of Medical Genetics, University of Washington , Seattle, Washington, USA ; Department of Pathology, University of Washington , Seattle, Washington, USA.
authors.forename: André
authors.initials: A
authors.lastname: Lieber