Epithelial junction opener JO-1 improves monoclonal antibody therapy of cancer

Area of Science:

• Oncology
• Molecular Biology
• Biotechnology

Background:

• Monoclonal antibody (mAb) therapy for solid tumors is often limited by intercellular junctions that restrict drug penetration.
• Targeting epithelial junction proteins is a potential strategy to enhance mAb delivery and efficacy.

Purpose of the Study:

• To investigate the efficacy of a novel protein, junction opener 1 (JO-1), in overcoming the barrier posed by intercellular junctions.
• To evaluate JO-1's potential to enhance the therapeutic efficacy of targeted mAbs in preclinical cancer models.

Main Methods:

• Developed and characterized JO-1, a recombinant adenovirus serotype 3-derived protein targeting desmoglein 2 (DSG2).
• Assessed JO-1's effect on DSG2 cleavage, E-cadherin expression, and tight junction integrity in cancer cell lines.
• Evaluated the impact of JO-1 on intratumoral penetration and therapeutic efficacy of anti-Her2/neu (trastuzumab) and anti-EGFR (cetuximab) mAbs in mouse xenograft models.

Main Results:

• JO-1 effectively cleaved DSG2 dimers, reduced E-cadherin expression, and loosened tight junctions.
• JO-1 significantly increased intratumoral penetration of trastuzumab and cetuximab, improving target receptor access.
• Combination therapy with JO-1 and mAbs demonstrated enhanced efficacy in breast, gastric, ovarian, and lung cancer models, with complete tumor eradication observed in some cases.

Conclusions:

• JO-1 is a potent agent for disrupting intercellular junctions in solid tumors.
• Combining JO-1 with mAb therapy represents a promising preclinical strategy to improve cancer treatment outcomes.
• Further clinical investigation of JO-1 in combination with antibody-based therapies is warranted.