A first-in-class precision antibody conjugate targeting EGFR, mTOR, and PI3K to treat head and neck cancers.

Head and neck squamous cell carcinoma (HNSCC) exhibits limited response to EGFR blockade with cetuximab, largely due to constant activation of the PI3K/AKT/mTOR pathways. Despite the development of numerous PI3K/mTOR inhibitors, their clinical application remains constrained by dose-limiting on-target toxicities. Here we report PAC-XL, a precision antibody conjugate linking the PI3K/mTOR inhibitor BGT226 to cetuximab through a β-glucuronidase-cleavable benzyl-ammonium carbamate (BAC) linker. Unlike conventional linkers, the BAC chemistry enabled a homogeneous, high drug-to-antibody ratio (DAR=8) conjugate that preserved EGFR binding, antigen-mediated uptake, lysosomal trafficking, plasma stability, and enzyme-dependent payload release. PAC-XL induced EGFR- and PI3K/mTOR-dependent cytotoxicity, suppressed PI3K/mTOR signaling, and triggered apoptosis in PIK3CA-altered HNSCC models. In xenografts, PAC-XL outperformed cetuximab, BGT226 and alpelisib, including complete regressions, while reducing hyperglycemia and weight loss caused by systemic PI3K/mTOR inhibition. These findings establish targeted delivery of PI3K/mTOR inhibitors as a strategy to enhance efficacy while improving tolerability in HNSCC.