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

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

  • Res Sq. 2026 May 14:rs.3.rs-9655840. doi: 10.21203/rs.3.rs-9655840/v1.
Xiaoyi Li 1,  Meghri Katerji 2 3 4,  Lily M Klapper 4,  Siddharth Matikonda 1,  Nick Brill-Edwards 4,  Aamna Siddiqui 4,  Chathuranga Rathnamalala 1,  Mo Yang 1,  Jungwuk Lee 4,  Ryan Bensen 4,  Lai Thang 5,  Simone Difilippantonio 5,  Julien Dugal-Tessier 6,  Shengzong Liang 6,  John Brognard 2 3 4,  Martin Schnermann 1
Affiliations

Affiliations

  • 1 Chemical and Biological Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702.
  • 2 Department of Surgery, Pharmacology, and Biochemistry and Molecular Biology, State University of New York, Upstate Medical University, Syracuse, NY 13210.
  • 3 Cancer Therapeutics Program, State University of New York, Upstate Medical University, Syracuse, NY 13210.
  • 4 Laboratory of Cell and Developmental Signaling, National Cancer Institute, National Institutes of Health, Frederick, MD 21702.
  • 5 Animal Technical Support, Laboratory Animal Sciences Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21702.
  • 6 NJ Bio Inc., Princeton, NJ 08540.
PMID: 42183362 DOI: 10.21203/rs.3.rs-9655840/v1
Abstract

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.

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