Translational development of a tumor junction opening technology.

Area of Science:

• Oncology
• Biotechnology
• Pharmacology

Background:

• Ovarian cancer often develops resistance to chemotherapy after initial response.
• Desmoglein-2 (DSG2) positive tight junctions in malignant cells impede drug penetration, contributing to resistance.
• Targeting these junctions is a strategy to overcome treatment resistance.

Purpose of the Study:

• To evaluate the clinical translation of c-JO4 in combination with Doxil for ovarian cancer therapy.
• To assess the safety and immunogenicity of c-JO4 in preclinical models.
• To investigate methods for managing immune responses to c-JO4.

Main Methods:

• cGMP manufacturing process developed for recombinant protein c-JO4.
• GLP toxicology studies in DSG2 transgenic mice and cynomolgus macaques.
• Combination therapy of c-JO4 with PEGylated liposomal doxorubicin (Doxil) in animal models, including immune response monitoring.

Main Results:

• cGMP-compliant c-JO4 produced with no observed toxicities in toxicology studies up to 24 mg/kg.
• Multiple cycles of c-JO4 plus Doxil induced anti-c-JO4 antibodies and pro-inflammatory cytokines (IL-6, TNFα).
• Steroid and cyclophosphamide pretreatment reduced antibody and cytokine responses.

Conclusions:

• c-JO4 shows potential for clinical translation in ovarian cancer therapy when combined with Doxil.
• Immune reactions (antibody production, cytokine release) to c-JO4 are a key consideration.
• Immune suppression strategies can mitigate adverse immune responses, suggesting acceptable safety with monitoring.