Translational development of a tumor junction opening technology

Abstract

Our goal is to overcome treatment resistance in ovarian cancer patients which occurs in most cases after an initial positive response to chemotherapy. A central resistance mechanism is the maintenance of desmoglein-2 (DSG2) positive tight junctions between malignant cells that prevents drug penetration into the tumor. We have generated JO4, a recombinant protein that binds to DSG2 resulting in the transient opening of junctions in epithelial tumors. Here we present studies toward the clinical translation of c-JO4 in combination with PEGylated liposomal doxorubicin/Doxil for ovarian cancer therapy. A manufacturing process for cGMP compliant production of JO4 was developed resulting in c-JO4. GLP toxicology studies using material from this process in DSG2 transgenic mice and cynomolgus macaques showed no treatment-related toxicities after intravenous injection at doses reaching 24 mg/kg. Multiple cycles of intravenous c-JO4 plus Doxil (four cycles, 4 weeks apart, simulating the treatment regimen in the clinical trial) elicited antibodies against c-JO4 that increased with each cycle and were accompanied by elevation of pro-inflammatory cytokines IL-6 and TNFα. Pretreatment with steroids and cyclophosphamide reduced anti-c-JO4 antibody response and blunted cytokine release. Our data indicate acceptable safety of our new treatment approach if immune reactions are monitored and counteracted with appropriate immune suppression.

In vivo HSC transduction in rhesus macaques with an HDAd5/3+ vector targeting desmoglein 2 and transiently overexpressing cxcr4

“…Furthermore, in the context of Investigational New Drug–enabling NHP studies with a modified recombinant Ad3 fiber knob (aka JO4) that also targets DSG2, we showed that DSG2 in normal epithelial tissues, which display a strict apical basal polarization, is trapped in lateral junctions and not accessible to IV injected ligands. 10, 53 This would imply that our DSG2-targeting HDAd5/3+ vectors would be safer compared with HDAd5/35++ vectors that target the ubiquitously expressed CD46 receptor. Furthermore, in contrast to HDAd5/35++ vectors, the use of HDAd5/3+ vectors would allow for adequate toxicology studies in NHPs, a prerequisite for the clinical translation of our approach for the treatment of nonmalignant diseases such as hemoglobinopathies.…”