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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 11, 2022
- Source ID
- 10.1038/s41598-022-11843-z
Entities
People
- André Lieber
- Arjun Raghuwanshi
- Audrey Baldessari
- Audrey Germond
- Bingmae Chen
- Chang Li
- Charles Drescher
- Darrick Carter
- Hongjie Wang
- Jiho Kim
- Laxman Savergave
- Pascal Fender
- Sanjay Singh
- Steve Roffler
- Sucheol Gil
- Swarnendu Kaviraj
Organizations
- National Institute for Health Care Management