Supramolecular Site-Specific Antibody Drug Conjugates Outperform Cysteine-Conjugated Analogs in Pancreatic Peritoneal Carcinomatosis

Antibody drug conjugates (ADCs) are a burgeoning class of targeted therapies. However, limitations in their synthesis and efficiency of payload delivery restrict their clinical utility. Here we report a supramolecular assembly (SMA) ADC conjugation method, which allows site-specific, uniform drug loading, resulting in an enhanced pharmacokinetic profile and in vivo efficacy. This peptide conjugation strategy relies on spontaneous heterotetrameric coiled-coil formation between a pair of peptides appended on the C-terminus and a drug-loaded complementary pair in aqueous solution. Pairing this SMA conjugation with an antibody that targets the dual-endothlin-1/VEGF signal peptide receptor (DEspR), a pancreatic ductal adenocarcinoma (PDAC) specific receptor, retains antibody binding and plasma stability. When the anti-DEspR monoclonal antibody is conjugated with monomethyl auristatin E (MMAE), the ensuing ADC internalizes following cell surface binding and induces selected cell death in multiple DEspR positive PDAC cell lines. In vivo , the ADC exhibits favorable pharmacokinetics, high tumor specificity, and improves overall survival in a rat orthotopic model of pancreatic peritoneal carcinomatosis, compared to conventional ADC conjugation. A heterotetrameric coiled-coil structure enables the efficient synthesis of a potent ADC, further documenting the versatility of supramolecular scaffolds as key orthogonal building block for site-specific conjugation in biopharmaceutical and biomaterial drug delivery systems.