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
  • 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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