Author:
Kim Jiho,Li Chang,Wang Hongjie,Kaviraj Swarnendu,Singh Sanjay,Savergave Laxman,Raghuwanshi Arjun,Gil Sucheol,Germond Audrey,Baldessari Audrey,Chen Bingmae,Roffler Steve,Fender Pascal,Drescher Charles,Carter Darrick,Lieber André
Abstract
AbstractOur 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.
Funder
DOD Peer Reviewed Cancer Research Program
Andy Hill CARE Fund
National Institute for Health Care Management Foundation
HDT Bio
Publisher
Springer Science and Business Media LLC
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