Structural Basis for Multivalent MUC16 Recognition and Robust Anti-Pancreatic Cancer Activity of Humanized Antibody...

Area of Science:

• Immunology
• Oncology
• Structural Biology

Background:

• Mucin-16 (MUC16) is a key target for antibody-based immunotherapies in pancreatic ductal adenocarcinoma (PDAC).
• The MUC16-specific antibody AR9.6 demonstrates promise for PDAC treatment and imaging.

Purpose of the Study:

• To structurally and biologically characterize the humanized AR9.6 antibody (huAR9.6).
• To evaluate the anti-PDAC efficacy of huAR9.6 in vitro and in vivo.

Main Methods:

• Determined the structure of huAR9.6 in complex with a MUC16 SEA domain.
• Assessed huAR9.6 binding to various forms of MUC16.
• Evaluated anti-PDAC activity in cell lines, patient-derived organoids (PDOs), and xenograft models.
• Investigated mechanisms including signal pathway blockade and immune-mediated cytotoxicity.

Main Results:

• HuAR9.6 binds a discontinuous MUC16 SEA domain epitope with 88 nmol/L affinity, influenced by glycosylation.
• Treatment with huAR9.6 inhibited PDAC cell growth, migration, invasion, and clonogenicity.
• HuAR9.6 blocked MUC16-mediated signaling, induced antibody-dependent cellular and complement-dependent cytotoxicity, and caused significant tumor regression in vivo.

Conclusions:

• HuAR9.6 demonstrates potent anti-PDAC activity through multiple mechanisms, including direct tumor cell inhibition and immune activation.
• The dense avid binding to MUC16 SEA domains is a potential mechanism of action.
• HuAR9.6 represents a promising therapeutic candidate for MUC16-positive PDAC.